TW201032806A - Hsp90 inhibitor combinations - Google Patents

Abstract

A pharmaceutical combination comprising an Hsp90 inhibitor and an mTOR inhibitor, and methods of using the combination to treat or prevent proliferative disorders.

Description

201032806 VI. Description of the Invention: [Technical Field] The present invention relates to a pharmaceutical composition comprising an Hsp90 inhibitor and an mTOR inhibitor, and the composition for treating a proliferative disease (more specifically, a mammalian ray Use of rapamycin dry standard (mTOR) kinase and its dependence on sexual diseases. Although there are many treatment options available for patients with proliferative diseases, there is a need for safe and effective anti-proliferative agents that require their use in combination therapies. φ It has now been found that a combination comprising at least one Hsp90 inhibitor compound and at least one mTOR inhibitor as described below has a beneficial effect on a proliferative disorder including, but not limited to, solid tumors, bone marrow-tumor, leukemia, stem Hemorrhoids, restenosis, scleroderma and fibrosis. ' This application claims to take precedence over the European application No. 08170279.7 filed on November 28, 2008, and the European application No. 08 170287.0 filed on November 28, 2008, filed on November 28, 2008. The contents of all of the four applications are incorporated herein by reference in their entire application Serial No. PCT Application Serial No. No. 08. [Prior Art] Heat shock protein 90 (Hsp90) is considered an anti-cancer target. The Hsp90 line is a ubiquitous key protein (1-2% of total cellular proteins) that can be used as a molecular companion protein to ensure conformational stability, shape and function of guest proteins. Among stress proteins, Hsp90 is unique because it is not required for most polypeptide biogenesis (Nathan et al., 1997). Its cellular target (also known as 144363.doc 201032806 as a guest protein) is a conformationally unstable signal transducer that plays an important role in growth control, cell survival and tissue formation (Pratt and Toft, 2003). Inhibits the intrinsic ATP of Hsp90. Enzymatic activity disrupts the Hsp90_ guest protein interaction, causing it to degrade via the ubiquitin proteasome pathway. Subtypes of Hsp90 guest proteins (eg, Raf, AKT, phospho-AKT, CDK4, and EGFR families, including ErbB2) are carcinogenic signaling molecules that play key roles in cell growth, division, and apoptosis, and these processes are for cancer cells. Very important. Degradation of one or more oncoproteins is believed to produce an anti-tumor effect observed using Hsp90 inhibitors. The Hsp90 family of chaperone proteins contains four members: Hsp90a and Hsp9〇P (both in the cytosol), GRP94 (in the endoplasmic reticulum), and TRAP1 (in the mitochondria) (Csermely et al., 1998). Hsp90 is the most abundant cellular chaperone protein, accounting for about 1% to 2% of total protein (Jakob and Buchner, 1994). The Hsp90 chaperone protein (Chene, 2002) with a conserved ATP-binding site at the N-terminal domain belongs to the small ATPase subfamily, which is called DNA gyrase, Hsp90, histidine kinase and MutL (GHKL). Subfamily (Dutta and Inouye, 2000). The chaperone (folding) activity of Hsp90 is dependent on its very weak ATPase activity on the isolated enzyme. However, it has been shown that when Hsp90 binds to a protein called a co-chaperone protein, the ATPase activity of Hsp90 is enhanced (Kamal et al., 2003). Thus, in vivo, the Hsp90 protein acts as a subunit of the large dynamic protein complex. Hsp90 is important for eukaryotic cell survival and is overexpressed in many tumors.

Treatment of cancer cells with mTOR inhibitors results in upregulation of the pro-survival protein phosphate-AKT 144363.doc 201032806 (O’Reilly, 2006). Since the phospho-AKT-based Hsp90 guest protein, co-treatment with an Hsp90 inhibitor prevents or reduces the upregulation of the phosphorylation-AKT induced by the mTOR inhibitor, thereby achieving an increase in antitumor effect. SUMMARY OF THE INVENTION In each of the examples, the pharmaceutical composition of the present invention comprises components (a) and (b) in a pharmaceutically acceptable carrier, wherein component (a) is a compound of formula (1)

Ra Ο

n^Y^n-R (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof, wherein

RaS is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) CVC6 alkoxy, (5) mercaptan, (6) CVC6 alkyl mercaptan, (7) substituted or Unsubstituted alkyl, (8) amino or substituted amine, (9) substituted or unsubstituted aryl, 144363.doc 201032806 (10) substituted or unsubstituted heteroaryl and (11) a substituted or unsubstituted heterocyclic group; R is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted C1-c6 alkyl, (3) substituted or unsubstituted C2-C6 alkenyl (4) Substituted or unsubstituted c2_C6 alkynyl, (5) substituted or unsubstituted 〇3-(:7-cycloalkyl, (6) substituted or unsubstituted (^-noncycloalkenyl, (7) a substituted or unsubstituted aryl group, (8) a substituted or unsubstituted heteroaryl group, and (9) a substituted or unsubstituted heterocyclic group; Rb is selected from the group consisting of: (1) substituted or Unsubstituted c3_c7 cycloalkyl, (2) substituted or unsubstituted (:5-(:7-cycloalkenyl, (3) substituted or unsubstituted aryl, (4) substituted or unsubstituted Aryl, and (5) substituted or unsubstituted a ring group; and the restriction is that if Ra is an amine group, Rb is not a phenyl group, a 4-alkyl-phenyl group, a 4-alkyloxyphenyl group or a 4-functional phenyl group, and the component (b) is a group. mTOR inhibitor. The compound of formula (I) may be combined with an mTOR inhibitor in a pharmaceutically acceptable carrier. In the method of treating a proliferative disease, the patient in need may be together or separately, simultaneously or sequentially A combination of an effective amount of a compound of formula (1) and a 144363.doc 201032806 mTOR inhibitor. In a preferred embodiment of the invention, a compound of formula (III) is provided as a first pharmaceutical component, The combination of mTOR inhibitors of the two medical components:

(III) or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof, wherein 1^ is selected from the group consisting of: (1) hydrogen, (2) i,

(3) thiol, (4) CVC6 alkoxy, (5) thiol, (6) CVC6 alkyl thiol, (7) substituted or unsubstituted Ci-Ce alkyl, (8) amine or Substituted amine group, (9) substituted or unsubstituted aryl, (10) substituted or unsubstituted heteroaryl, and 144363.doc 201032806 * (Π) substituted or unsubstituted heterocyclic group; R54 Is chlorine or substituted or unsubstituted Cl-c6 alkyl; 'is hydrogen, alkyl, alkoxy, or deuterated;; R7, R1R9 are each independently selected from hydrogen, alkyl, methoxy, a group consisting of: a substituted group, a substituted (tetra) group, and a (four) unsubstituted quinone group; or

"A stereoisomer, tautomer, pharmaceutically acceptable salt thereof, or pre-existing, and the limitation is that if R, an amine group and R6, R7, R8 and R9 are hydrogen, then R may not be hydrogen or an alkane. Alkoxy, alkoxy, or halo. In certain embodiments, a compound of formula (IIIa) is provided:

Or a tautomer thereof, a pharmaceutically acceptable salt, or a prodrug thereof, wherein Ra, R4, R5, R6, R7, R8 and R9 are as defined above for formula (m) and the restriction is if 1^ Is an amine group and R6, R7, uldent 8 and R9 are hydrogen, and R5 is not hydrogen, alkyl, alkoxy, or methine.

In certain embodiments, Ra is hydrogen. In certain embodiments 'Ra is a substituted or unsubstituted Cl-C6 alkyl group. 144363.doc 201032806 In certain embodiments, 1 is (: 1_(: 6 alkyl or halogenated Ci_C6 alkyl. In certain such embodiments, Ra is methyl. Certain embodiments of the invention In the example, 'R4 is selected from the group consisting of hydrogen, benzyl, b-(4-methoxyphenyl)ethyl, methyl, 3-aminopropyl and 2-methyl-2-morpholinylpropyl. In other embodiments, R is selected from the group consisting of methyl, ethyl, allyl, 3-methyl-butyl, and isobutyl. In certain embodiments 'R5 is hydrogen or fluoro. In some embodiments, R5 is fluoro. In certain embodiments, R5 is methyl or methoxy. In certain embodiments, R7, R8, and R9 are each hydrogen. In certain embodiments, the 'R6 system An aryl or heteroaryl group may be substituted with 1 to 2 substituents selected from the group consisting of halo, alkoxy, alkyl, amine, alkylamino, alkyl, and haloalkoxy. In certain embodiments, R6 is selected from the group consisting of substituted aryl and substituted heteroaryl, wherein the aryl and heteroaryl are selected from the group consisting of: σ-fumonyl, ° σ Base, phenyl, thiol base, bis-azine Base, mouth bite, pyridazinyl, pyrazolyl, imidazolyl, triazolyl, fluorenyl, σoxadiazolyl, thiadiazolyl, quinolyl 'isoquinolyl, isoxazolyl, Chewing thiol, oxazolyl and thienyl. In some aspects, the above groups may be selected from 1 to 2 selected from a dentate group, an alkoxy group, a leukoyl group, an amine group, a aryl group, a tooth generation. Substituent substituents of the group consisting of alkyl and haloalkoxy groups. In other embodiments, R6 is selected from the group consisting of: (2-hydroxy-ethylamino)-pyr-2-yl, lH- η ratio ° sit-4-yl, 1-mercapto-lH-n ratio σ sit _4· base, 1-mercapto-111-0 ratio ° sit-4-yl, 2-(5-methyl 嚏_2-yl)-phenyl, 144363.doc -9- 201032806 2,3-difluoro-phenyl, 2,3-dimethoxyoxyphenyl, 2,4-difluoro-phenyl, 2, 4-dimethoxy-phenyl, 2,4-dimethoxy-pyrimidin-5-yl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-di Methyl-pyridin-3-yl, 2-ethylamidophenyl, 2-aminophenyl, 2-amino-13-pent-5-yl, 2-chloro-4-methoxy- Xiaoxiao-5-based, 2-gas-5-gas-D ratio -3-yl, 2- gas-phenyl, 2-chloro-pyridine-3-yl, 2- - aridin-4-yl, 2-difluoro-3-indolylphenyl, 2-ethyl-phenyl, 2-ethoxy-thiazol-4-yl, 2-fluoro-3-indolyloxy -phenyl, 2-fluoro-3-indolylphenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-methoxy-phenyl, 2·fluoro-5-nonylphenyl , 2-gas phenyl, 2- gas-σ ratio acetyl-3-yl, 2-carbomethyl-3-methoxyoxyphenyl, 2-hydroxymethylphenyl, 2-isoquinoline-4- , 2-decyloxy-5-triptanyl-phenyl, 2·methoxy-phenyl, 2-methoxy-0-precipitate-3-yl, 2-decyloxy-pyrimidine-4 -yl, 2-methoxy-thiazol-4-yl, 2-methyl-phenyl, 2-indenyl. ratio. Determine the 3-amino group, 2-o-oxy-1,2-dipho-pyr ratio. 3--3-yl, 2-phenylphenylphenyl, 2-oxaridin-3-yl, 2-pyrimidin-5-yl, 2-trifluoromethoxyphenyl, 2-trifluorodecyloxy-benzene , 3,4-dimethoxy-phenyl, 3,5-dimethyl-isoxazol-4-yl, 3,6-dimercapto-pyrazin-2-yl, 3-acetamidamine Phenylphenyl, 3-aminocarbophenyl, 3 -> odor-phenyl, 3- gas-° ratio 0-methyl-2-yl, 3-oxyl phenyl, 3-dimethylamino Phenyl, 3-ethylidyl-phenyl, 3-ethyl-4-indolyl-phenyl, 3-ethylhexyl-phenyl, 3- gas-6-methyllacyl-. Ratio 定-2-yl, 3- gas phenyl, 3-fluoro-pyridazin-2-yl, 3-methanesulfonylaminophenyl, 3-methoxycarbonylphenyl, 3-methoxybenzene , 3-methoxy-pyridazin-2-yl, 3-mercapto-3Η-imidazo[4,5-b]pyrazin-5-yl, 3-nonylphenyl, 3-indenyl- Pyridin-2-yl, 3-trifluoromethoxyphenyl, 3-trifluorodecylphenyl, 4,5-dimethoxyoxy-pyrimidin-2-yl, 4-amino-5-gas- whistling -2--2-yl, 4-chloro-2,5-dimethoxy-phenyl, 4_ I44363.doc - 10- 201032806 gas-2-fluoro-phenyl, 4-vapor-2-methoxy-5 -Methyl-phenyl, 4-chloro-indolepyridin-3-yl, 4·di-2-methyl-phenyl, 4-ethoxy-5*-rat-biting 2-base, 4 -ethoxy-choke-2-yl, 4-ethoxy, 4-ethylbi-3-yl, 4-fluoro-2-methoxy-phenyl, 4-fluoro-2-methyl -Phenyl, 4-fluorophenyl, 4-methoxy-5-methyl-pyrimidin-2-yl, 4-methoxy-pyridin-3-yl, 4-methoxy-pyrimidine-2- , 4-methoxy-pyrimidin-5-yl, 4-methyl-phenyl, 4-methyl-pyridin-2-yl, 4-methyl-pyridin-3-yl, 4-pyrrolidine-1 _ base_ shy-2-yl, 5,6-dimethoxy-pyrazin-2-yl, 5-ethenyl-thiophen-2-yl, 5-amino-6-ethoxy-D Ratio ββ-2-yl, 5-amino-6-methoxy·3-methyl-oxime ratio u桊-2-yl, 5-amino-6-methoxyl-butyl-2-yl, 5-A-4-methoxy methoxy-2-yl, 5- gas-6-methoxy-σ bis-2-yl, 5-monodecylamino-6-methoxy-°嗓-2-yl, 5-fluoro-2-methoxyphenyl, 5-fluoro-4-methoxy-spray-_2-based, 5- gas-6-methoxy-σ- 2-based, 5- gas ratio bit-2-yl, 5-methoxy-3-pyridin-3-yl, 5-methoxy-thiophen-2-yl, 5-trifluorodecyl-pyrimidine-2 -6,6-ethyl-based-π ratio bit-2-yl, 6-chloro-^ is a 2-yl group, 6-ethoxy-β is-2-yl, 6-ethoxy-yl , 6 - gas - Dtt ° -2 - base, 6-gas ratio bite - 3-base, 6-carbyl-to-pylory-2-yl, 6-methoxy-5-methylamino group - ° -2--2-yl, 6-methoxy-5-methyl phthalazin-2-yl, 6-methoxypyrazin-2-yl, 6-methoxy-° ratio. -2 - yl, 6 · methoxy- ° ratio -3 - group, 6 - methylamino - 吼嘻 - 2 - group, 6 - methyl - 0 - dec-2-yl, 5 -Amino-6-(2,2,2-dioxaethoxy)indole is a 2-yl group and a 6-trifluoromethyl-pyridine-2-yl group. The present invention also relates to the use of an Hsp90 inhibitor such as the following: the isoxazole derivative of the formula (1)) and its regioisomers as well as salts, solvates and hydrates thereof, and prodrugs thereof 144363.doc-11 201032806

(D) wherein each R independently represents an optional substituent and R3 represents a carboxyguanamine group. Combinations of the invention include compounds that target, reduce or inhibit the activity/function of the serine/threonate mTOR kinase. Such compounds may be referred to as "mTOR inhibitors" and include, but are not limited to, compounds, proteins or antibodies that target/inhibit members of the mTOR kinase family, eg, RAD, rapamycin (sirolimus) and Derivatives/analogs, for example, everolimus or RAD001. Sirolimus is also known by the name RAPAMUNE and is known by the name CERTICAN of everolimus or RAD001. Other compounds, proteins or antibodies that target/inhibit members of the mTOR kinase family include CCI-779, ABT578, SAR543 and ascomycin, which are ethyl analogs of FK506. Also included are AP23573 and AP23841 from Ariad. Preferred mTOR inhibitors are everolimus, rapamycin, ascomycin and rapamycin derivatives. [Embodiment] The following definitions are provided to better understand the present invention. "Alkyl" or "unsubstituted alkyl" means a saturated hydrocarbon group which does not contain a hetero atom. Thus, the term includes straight-chain alkyl groups such as, for example, fluorenyl, ethyl, propyl, butyl, decyl, hexyl, heptyl, octyl, decyl, decyl, 144, 363.doc -12- 201032806 Alkyl, dodecyl and the like. The term also includes branched isomers of linear alkyl groups including, but not limited to, the following groups provided by way of example: -CH(CH3)2, -CH(CH3)(CH2CH3), -CH ( CH2CH3)2, -c(ch3)3, -c(ch2ch3)3, -ch2ch(ch3)2, -ch2ch(ch3) • (ch2ch3), -ch2ch(ch2ch3)2, -ch2c(ch3)3,- Ch2c (CH2CH3)3, -ch(ch3)ch(ch3)(ch2ch3), -ch2ch2ch(ch3)2, -ch2ch2ch(ch3)(ch2ch3), -ch2ch2ch(ch2ch3)2, -ch2ch2c(ch3)3,- Ch2ch2c(ch2ch3)3, -ch(ch3)ch2ch Φ(ch3)2, -ch(ch3)ch(ch3)ch(ch3)2, -ch(ch2ch3)ch(ch3)ch(ch3)(ch2ch3), and others. Thus, the term "alkyl" includes primary alkyl, secondary alkyl and tertiary alkyl. Preferred alkyl groups include straight chain and branched alkyl groups having from 1 to 12, from 1 to 6, or from 1 to 3 carbon atoms. "Alkyl" or "unsubstituted alkyl" means the same residue as described above for "alkyl" but having two points of attachment. Exemplary alkylene groups include ethyl (-CH2CH2-), propyl (-CH2CH2CH2-) and dimethyl propyl (-CH2C(C H3) 2CH2-). "Alkenyl" or "unsubstituted alkenyl" means a straight-chain or branched hydrocarbon group having one or more carbon-carbon double bonds and having from 2 to about 20 carbon atoms. Preferably, the alkenyl group includes a linear and branched, dilute group having 2 to 12 or 2 to 6 carbon atoms. "Quick base" or "unsubstituted alkynyl" means a straight-chain or branched hydrocarbon group having one or more carbon-carbon triple bonds and having from 2 to about 20 carbon atoms. Preferred alkynyl groups include straight chain and branched alkynyl groups having 2 to 12 or 2 to 6 carbon atoms. 144363.doc •13· 201032806 “Cycloalkyl" or “unsubstituted ring” means a monocyclic or polycyclic alkyl substituent. Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentylcyclohexyl, cycloheptyl and cyclooctyl. Preferred cycloalkyl groups have from 3 to 7 carbon atoms. "Cycloalkenyl" or "unsubstituted cycloalkenyl" refers to a monocyclic or polycyclic alkyl substituent having at least one cyclic carbon-carbon double bond. Preferred cycloalkenyl groups have 5 to 7 carbon atoms and include cyclopentenyl and cyclohexenyl. "Substituted alkyl" means an alkyl group as defined above wherein one or more carbon bonds or hydrogen bonds are replaced by a non-hydrogen atom or a non-carbon atom such as, but not limited to, the following: halogen atom , for example, F, C1, ^, and work; oxygen Z-substituents in groups such as hydroxyl, alkoxy, aryloxy, and ester groups; present in such groups as thiol groups, alkyl sulfides, and aromatics a sulfur atom in a group such as a thioether, an anthracene, a sulfonyl group or an anthracene group; and is present in, for example, an amine group, a arylamino group, an alkylamino group, an arylamino group, an alkylarylamino group, a nitrogen atom in a group such as an arylamine group, an N-oxide, a quinone imine, and an enamine. Substituted groups also include oxygen in which one or more carbon atoms or hydrogen atoms are bonded via a hetero atom such as 'in the pendant oxy group, a few groups, a slow group, and a vine group; or in an imine such as an imine Nitrogen in a group such as hydrazine and nitrile) a group in which a higher bond (for example, a double bond or a triple bond) is substituted. The substituted alkyl group further includes an alkyl group in which one or more carbon atoms or hydrogen atoms are bonded via an aryl group, a heteroaryl group, a heterocyclic group, a ring-based group or a cycloalkenyl bond. Preferred substituted alkyl groups include, in particular, a group of = or - or a plurality of carbon atoms or hydrogen atoms bonded via one or more gas, gas or radical linkages. Another preferred substituted group is the tridontyl group and other alkyl groups containing a trifluoromethyl group. Other preferred substituted alkyl groups include 144363.doc -14· 201032806 alkyl groups in which one or more carbon atoms or hydrogen atom bonds are replaced via oxygen atom bonding such that the substituted alkyl group contains a hydroxyl group, an alkoxy group. Base or aryloxy. Other preferred substituted alkyl groups include those having an amine group, or a substituted or unsubstituted alkylamino group, an arylamino group, a heterocyclic amino group. Other preferred substituted alkyl groups include those wherein one or more of the carbon or hydrogen atoms are bonded via an aryl, heteroaryl, heterocyclyl or cycloalkyl linkage. Examples of substituted alkane groups are: -(ch2)3nh2, -(ch2)3nh(ch3), -(ch2)3nh(ch3)2, -CH2C(=CH2)CH2NH2, -CH2C(=0)CH2NH2' -ch2s(=o)2ch3, -ch2och2nh2, -ch2co2h. Examples of the substituent of the substituted alkylhydrazine are: -CH2OH, -OH, -OCH3, -OC2H5, -0CF3' oc(=o)ch3, -oc(=o)nh2, -oc(=o)n( Ch3)2, -CN, -no2, -c(=o)ch3, -co2h, -co2ch3, -CONH2, -NH2, -N(CH3)2, -NHSO2CH3 '-NHCOCH3 > -NHC(=0) OCH3, -NHSO-2CH3, -so2ch3, -so2nh2 and a tooth base. The "substituted alkenyl group" generally has the same meaning as the unsubstituted alkyl group as compared with the unsubstituted alkyl group as compared with the unsubstituted alkyl group. The substituted alkenyl group includes an alkenyl group in which a non-carbon atom or a non-hydrogen atom is bonded to a carbon which is double-bonded to another carbon atom, and one of the non-carbon atoms or a non-hydrogen atom thereof is bonded to the other An alkenyl group of a carbon of a double bond of a carbon atom. - "Substituted alkynyl" has the same meaning as unsubstituted alkynyl as substituted alkyl. The substituted alkynyl group includes an alkynyl group in which a non-carbon atom or a non-hydrogen atom is bonded to a carbon bonded to another carbon atom by a triple bond, and one of the non-carbon atoms or a non-hydrogen atom is bonded to another carbon. The fast radical of the carbon of the three bonds of the atom. The "substituted cycloalkyl group" has the same meaning as the unsubstituted alkyl group with respect to the unsubstituted alkyl group as compared with the unsubstituted alkyl group as the substituted alkane 144363.doc -15-201032806. The "substituted cycloalkenyl group" has the same meaning as the unsubstituted alkyl group as compared with the unsubstituted alkyl group, as compared with the unsubstituted alkyl group. "Aryl" or "unsubstituted aryl" means a monocyclic or polycyclic aromatic group which does not contain a ring hetero atom. These groups may contain from 6 to 14 carbon atoms but preferably contain 6 carbon atoms. Exemplary aryl moieties for use as substituents for the compounds of the invention include phenyl, phenyl, and the like. "Aralkyl" or "arylalkyl" means an alkyl group substituted by an aryl group as defined above. Generally, the aralkyl group used in the compound of the present invention has from 丨 to 6 carbon atoms incorporated in the alkyl portion of the aralkyl group. Suitable aralkyl groups for use in the compounds of the invention include, for example, benzyl and the like. "Heteroarylalkyl" or "heteroaryl" refers to a radical substituted with a heteroaryl group as defined above. Usually, the heteroarylalkyl group used in the compound of the present invention has from ～ to 6 fluorene atoms incorporated in the alkyl moiety of the aralkyl group. Suitable heteroarylalkyl groups for use in the compounds of the invention include, for example, pyridinium and the like. "Alkoxy" means R20〇- wherein R20 is C^C:7 alkyl or substituted alkyl. In certain embodiments, r2〇 is a Cl_C6 alkyl group. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, trifluoromethoxy and the like. "Amine" refers herein to the group νη2. "Substituted amine group" means a group wherein the ruthenium 6 and R61 are independently selected from the group consisting of -NR6GR61: hydrogen, alkyl 'substituted alkyl, alkenyl, substituted alkenyl, alkynyl, Substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, 144363.doc •16· 201032806 substituted heterocyclic, S〇2-alkyl, -S〇2_substituted alkyl; and wherein r6〇 and R61 are bonded to the nitrogen atom to which they are bonded to form a heterocyclic group or a substituted heterocyclic group, the limitation is R6G and None of them are hydrogen. In the case of chlorine and R61 is an alkyl group, the substituted amine group is often referred to herein as an alkylamine group. If both R60 and R61 are alkyl groups, substituted amino groups are often referred to herein as dialkylamino groups. When referring to a single substituted amine group, it means that r6? or R is hydrogen but the two are not simultaneously hydrogen. When referring to a twice substituted amino group, it means that neither R6G nor R61 is hydrogen. The term "alkylamino group" as used herein refers to a group wherein the aryl group is C^C7 alkyl and the group R60 is hydrogen or a group -nr60r61. The term "dialkylamino" refers to a group -NrMrM wherein R6 and R6 are both CVC7 alkyl. The term "arylamino" as used herein refers to a group -NR60R61 wherein R60 is CVC7 aryl and r6 is hydrogen, Ci_C7 alkyl or c5_C7 aryl. The term "aralkylamino" as used herein refers to a group -NR6()R61 wherein R60 is aralkyl and R61 is hydrogen, Cl_C7 alkyl, eye? aryl or CrC? arylalkyl. "脒" means R40-C(=N)-NR41- (the group is located at the "Nl" nitrogen atom) and R,NR41)C=N_ (the group is at the "n2" nitrogen atom) Wherein R41R41 can be hydrogen, Ci_C7 leukoyl, aryl or (:5-(:7 arylalkyl). "Alkoxyalkyl" system, which refers to the system Ci_c7 alkyl and is called c]_c7 alkyl The group -alkrO-aikr the term "aryloxyalkyl" refers to the group _ (Ci-C7 alkyl)-0-(C5-C7 aryl). "Alkoxyalkylamino" is used herein. Refers to the group _NR27_(alkoxyalkyl), wherein R27 is typically hydrogen, C5_C7 aralkyl 4Ci_C7 alkyl. 144363.doc •17- 201032806 "Aminocarbonyl" refers herein to the group -c(o -NH2. "Substituted aminocarbonyl" refers herein to the group -c(o)-nr28r29, wherein R28 is a GC7 building group and R is hydrogen or a deutero. The term "arylaminocarbonyl" is used herein. Wherein R3 is a Cs_C7 aryl group and R3 is a hydrogen, alkyl or CVC:7 aryl group. "Aralkylaminocarbonyl" refers herein to the group -C(0)NR32R33, Wherein R32SC5_C7 aralkyl and R33 is a gas, (VC7 alkyl, C5_C7 aryl or C5_C7 aralkyl. "Aminosulfonyl" as used herein refers to the group -s(o)2-nh2. "Substituted amine aryl" is used herein to mean that r34 is Ci_c7, and r35 is hydrogen or CVC7 alkyl. The group _s(〇)2_NR34R35. The term "aralkylamino-aryl-aryl" refers herein to the group -(c5-c7aryl)-s(o)2-NH-aralkyl "Aroyloxy" means r5〇〇_ wherein 5 〇 is an aryl group. "Carbonyl" means a divalent group _c(0)_. "Alkylcarbonyl" means a group _ c(o "Alkylcarbonyl" means a group _c(〇)aryl. Similarly, the terms "heteroaryl", "arylalkyl" and "heteroaryl" are used. Refers to ❹-C(0)-R, wherein R is heteroaryl, aralkyl and heteroarylalkyl. "Carboxyoxy" generally refers to the group _c(0)_o_. These groups include Ester, -c(o)-〇-R36, wherein r36 is c] c7 alkyl, cycloalkylaryl or Cs-C? arylalkyl. The term "arylcarbonyloxy" is used herein to mean - group -C(0)-0-(aryl). The term "aralkylcarbonyloxy" as used herein refers to the group -C(〇)-〇-(c5-c7 aralkyl). 5 alkylene alkyl" means A cycloalkyl-substituted alkyl group as defined above. 144363.doc -18· 201032806 Typically, a cycloalkylalkyl group has 1 to 6 carbon atoms incorporated in the alkyl moiety of the cycloalkylalkyl group. "Amine" means a divalent group c(o). wherein the hydrogen atom of the guanamine nitrogen of the carbonylamine group can be replaced by a ruthenium-heart-burning group, an aryl group or a Cs-C7 aryl group. The carbonylamino group includes a moiety such as a urethane (_NH_c(〇)_〇_R28) and a guanamine-NH-C(0)R28, wherein R28 is a linear or branched heart-...alkyl group, Cs-C7 cycloalkyl, or aryl or C5_C? aralkyl. The term "alkylaminoamino" refers to the group -NH-C(0)-R28', wherein R28' is an alkyl group having from 1 to about 7 carbon atoms in its backbone structure. The term "arylalkylamino" refers to a group wherein NH9 is a CVC7 aryl group. NH-qc^R29. Similarly, the term "aralkylcarbonylamino" refers to a carbonylamino group wherein the 29 is a c5-C7 aralkyl group. "Guanidino or guanidyG" means a moiety derived from hydrazine, h2n_C(-NH)-NH2, and such moieties include those which are bonded at the nitrogen atom carrying the carboxylic acid double bond (胍"2" _ position, for example, diamino sulfhydrylamino group, (H2N) 2C = NH-) and the moiety which is bonded at any nitrogen atom carrying a single chain of a acetal aldehyde (胍"1"_ and / or "3"_ position, for example, H2N-C(=NH)-NH-: ^ The hydrogen atom at any nitrogen atom may be via a suitable substituent (such as Ci-C7 alkyl, aryl) Or (:5_(:7 aralkyl) is substituted. "Yu" or "halo" refers to gas, bromine, fluorine and moth groups. The term "haloalkyl" refers to one or more functional atoms. Substituted alkyl group. "Halo-substituted" group includes -CF3. The term "haloalkoxy" means an alkoxy group substituted by one or more halogen atoms. "Tooth alkoxy" group 144363.doc -19· 201032806 The group includes -OCF3 and _〇ch2CF3. "Hydroxyl or hydroxy" means a group. "Heterocyclyl" or "unsubstituted heterocyclic ring" is used herein. "unsubstituted And "heterocyclic group" or "unsubstituted ring group", "heterocyclic compound group" or "unsubstituted heterocyclic group" are used in humans, and are selected from heteroatoms of nitrogen, oxygen or sulfur. Ring or polycyclic non-quinone = compound. Examples include a heteroatom containing a nitrogen, oxygen and sulfur = ring or a member or a 6 membered ring containing (1) a hetero atom selected from the group consisting of nitrogen, oxygen or sulfur; Wherein the 5-membered ring has 0 to 1 double bond and the 6-membered ring has 〇2 double bonds; wherein the nitrogen atom and the sulfur atom may be oxidized as appropriate; wherein the nitrogen and sulfur heteroatoms may pass through four stages as the case may be. And includes any-bicyclic group in which the above-mentioned V heterocyclic ring is fused to the benzene ring or another-independently independent H-shaped ring, with the proviso that the point of attachment is via a heterocyclic ring. The cyclic moiety can be substituted, for example, one or two times, independently, independently of, but not limited to, each of the following substituents: a benzyl group, an alkoxy group, a decyl group, a pendant oxy group (c=o), an alkyl group. Amino group (rmn=, wherein R" is alkyl or alkoxy), amine group, alkylamino group, mercaptoamine group, alkoxy group, thioalkyloxy group, polyalkoxy group, alkyl group , Alkyl or a Southern alkyl group. The heterocyclic groups can be attached at various positions as shown below, as will be understood by those skilled in the art of organic chemistry and medicinal chemistry in conjunction with the disclosure herein. Μ

0〆 X) οώ Α Υ 144363.doc •20- 201032806

Wherein R is an anthracene or heterocyclyl substituent, as described herein. "Heteroaryl" and "unsubstituted heteroaryl" refer to an aromatic group having 1 to 4 hetero atoms as a ring atom in the ring, the yarn atomic carbon atoms. The term "heteroaryl" includes a material in which the nitrogen system is a tetrazole and a ++ ring structure (d) (4) and a fully saturated ring, such as 'the present oxazolyl group (which has a heterocyclic group slightly bonded to the phenyl group). The knot is 'restricted to the point that the point of attachment is via a heteroaryl ring. The heteroaryl group can be substituted and can be attached at various positions, as will be understood by those skilled in the art of organic chemistry and medicinal chemistry. Representative, substituted and unsubstituted heteroaryl groups include, for example, the heteroaryl groups found in the compounds disclosed in the examples and the examples shown below.

CI 144363.doc 21 201032806

NH

N a N ‘

A preferred heterocyclic and heteroaryl group has 3 to 14 ring atoms and includes, for example, a 2 nitrogen group, a base group, a base group, a (tetra) group, a (four) bite group, and a taste base. Than base, hexachloropurine bite " thiol, flavonoid, oxetyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyloxazolidine, Morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furan , thiophenyl, triazolyl, quinoxalinyl, pyridazinyl, naphthylpyridyl, oxazolyl and benzothienyl 0 heteroarylalkyl or "heteroaralkyl" means A heteroaryl-substituted alkyl group as defined above. Typically, the heteroarylalkyl group has from 1 to 6 carbon atoms incorporated into the alkyl moiety of the heteroarylalkyl group. "Imino" means a group = NH. "Nitro" means the group N02. 144363.doc •22- 201032806 “Items” refers to the base L in this article. "Reduced brewing base" refers to the structure in which the R52-based Cl-C7 appearance group is replaced by the _s〇2r52'. The alkyl group to be used in the compound of the present invention is usually a hospital base having 1 to 6 carbon atoms in its primary bond structure. Therefore, the typical thiol group in the compound of the present invention includes (Example >). The thiol group (i.e., wherein R52 is a fluorenyl group), an ethyl sulfonyl group (i.e., wherein R52 is B a propyl sulfonyl group (ie, wherein R52 is a propyl group) and the like. The term "aryl thiol" as used herein refers to the group -so2-aryl. The term "heterocyclic base" refers to the group SG2.heterocyclic group in the present x. The term "arylalkylsulfonyl" as used herein refers to the group -S02-aralkyl. The term "sulfonamide" refers herein to _S〇2NH2. The term "sulfonamidoalkyl" means (alkyl)S02NH2-. "Thio or thiol" refers to the group _SH. "Alkylthio or alkylthiol" refers to a thiol group substituted with an alkyl group (e.g., an alkyl group). "Thiodecylamino" refers to the group -C(=s)NH2. "Substituting as appropriate" means that hydrogen may be replaced by a monovalent or divalent group. "Substituted" means that hydrogen can be replaced by a monovalent or divalent group. Unless otherwise stated, 'suitably suitable substituents include, for example, hydroxy' alkoxy, nitro, amide, imino, cyano, dentate, thio, sulfonyl, thioguanamine Base, fluorenyl, pendant oxy, amidino, methylamine, sulfhydryl, sulfonylamino, carboxy, methionyl, alkyl, dentylalkyl, alkylamino, haloalkylamine Base, alkoxy group, halogenated alkoxy group, alkoxy-alkyl group, alkylcarbonyl group, aminocarbonyl group, arylcarbonyl group, aralkylcarbonyl group, heteroarylcarbonyl group, heteroarylalkyl-carbonyl group, alkyl group Sulfur, aminoalkyl, cyanoalkyl, aryl and 144363.doc -23- 201032806 and the like. Other suitable substituent groups include those which are indicated for the substituted alkyl group. Examples of suitable substituent groups are also found with reference to the compounds disclosed throughout this application. The substituent group itself can be substituted. The substituent on the substituent group may be a carboxyl group, a carboxy group, a nitro group, an amine group, a cyano group, a hydroxyl group, an alkyl group, an alkoxy group, an aminocarbonyl group, -SR42, a thioguanamine group, -S03H, S02R42. Or a cycloalkyl group wherein R42 is typically hydrogen, hydroxy or alkyl. If the substituted substituent includes a linear group, the substitution may occur in the chain (eg, 2-hydroxypropyl, 2-aminobutyl, and the like) or at the end of the chain (eg, 2-hydroxyl) Ethyl, 3-cyanopropyl and the like). The substituted substituent may be a linear, branched or cyclic arrangement of covalently bonded carbon atoms or heteroatoms. Unless otherwise indicated, the nomenclature of substituents not specifically defined herein may be obtained by sequentially naming the terminal moiety of the functional group and the adjacent anthracene group towards the point of attachment. For example, the substituent "alkoxyheteroaryl" refers to a group (alkoxy)-(heteroaryl). The preferred compound of formula (1) used in the present invention has less than 1000 Daltons, preferably less than 750 Daltons. The total molecular weight of the compound. The compound of formula (1) typically has a minimum molecular weight of at least 150 Daltons. Preferably, the compound of formula (I) has a molecular weight between 15 〇 Daltons and 750 Daltons' and in a more preferred embodiment There is a molecular weight between 200 Daltons and 5 Daltons. Other embodiments of the invention include the use of a compound of formula (1) having a molecular weight between 3 Daltons and 450 Daltons. In another aspect of the invention, the compound of formula (I) used in the present invention has a molecular weight of 144363.doc 201032806 between 35G Daltons and Pedalton. Similarly, it should be understood that the above definition does not This includes substitution patterns that are not possible (for example, methyl groups substituted with 5 fluoro groups). Such substitution patterns that are not possible are well known to those skilled in the art. • "Carboxy-protecting group" refers to An ester group commonly used to protect carboxylic acids. Esterified carbonyl groups The ester group can be used to block or protect the carboxylic acid functional group when the other functional sites of the compound participate in the reaction. Further, the carboxy protecting group can be attached to the solid phase carrier, thereby allowing the compound to be hydrolyzed in the carboxylic acid ester. The φ method dissociates to remain attached to the solid support prior to releasing the corresponding free acid. Representative carboxy-protecting groups include, for example, alkyl esters, secondary guanamines, and the like. Certain compounds of formula (I) contain asymmetric substitutions. Carbon atoms. The asymmetrically substituted carbon atoms may allow a compound of the invention to comprise a mixture or a single stereoisomer of a stereoisomer at a particular asymmetrically substituted carbon atom. Thus, the invention includes, in addition to a compound of the invention Racemic mixture, enantiomeric mixture, and enantiomer. The terms "S" and "R" are used herein as IUPAC 1974 "RECOMMENDATIONS FOR SECTIONE, FUNDAMENTAL STEREOCHEMISTRY," Pwre 4/7 households. CTzem. - 45:13-30, defined in 1976. The terms α and β are used for the ring of a cyclic compound. Positioning. The side of the reference plane is located above its preferred substituent. The side of the small numbered position. The substituents on the opposite side of the reference plane are assigned a beta descriptor. It should be understood that this usage is different from the usage of the circular solid parent in which "a" means "below the plane" and its indication Absolute configuration. The terms a and β are used herein as defined in the "Chemical Abstracts Index Guide," (Appendix 144363.doc -25- 201032806 IV, paragraph 203, 1987). The term "medically acceptable" is used herein. "Salt" means a non-toxic acid or alkaline earth metal salt of the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5one compound of the present invention. These salts can be prepared in situ during the final isolation and purification of the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5one compound or by means of an acid or functional group It is prepared by reacting independently with a suitable organic or inorganic acid or base. Representative salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate , camphorate, camphor sulfonate, digluconate, cyclopentane propionate, lauryl sulfate, ethane sulfonate, glucoheptonate, glycerol phosphate, hemisulfate, g Acid, hexanoate, fumarate, hydrogenate, hydrobromide, hydromomate, 2-hydroxyethyl citrate, lactate, maleate, methane sulfonate, nicotine Acid salt, 2-naphthalene sulfonate, oxalate, bamotate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, amber Acid salts, sulfates, tartrates, thiocyanates, p-toluenesulfonates and undecanoates. Moreover, the 'initial nitrogen-containing group can also be quaternized with a reagent such as the following: an alkyl halide, for example, a vapor, a bromide and an iodide of a methyl group, an ethyl group, a propyl group and a butyl group; a dialkyl sulfate group; Esters such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain derivatives, for example, sulfhydryl, lauryl, meat ugly and stearyl vapors, bromides And iodide; aromatic Hyun-based dentate', for example, agglomerate and phenethyl bromide; and others. This results in a water or oil soluble or dispersible product. Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include 144363.doc 201032806 organic acids (eg 'hydrogen acid, sulfuric acid and phosphoric acid) and organic acids (eg oxalic acid, maleic acid, formic acid, Break the acid and citric acid). The addition salt can be prepared in situ during the final separation of the 2-amino 7,8-hydro-6H-pyrido[4 3 d]pyrimidin-5 ketone compound or by making the carboxylic acid moiety with a suitable base ( For example, 4 drugs can be prepared by reacting the metal hydroxide ions of the metal cesium ions, carbonate or hydrogen carbonate-magic or with ammonia, or -grade, secondary or tertiary organic amines. Including, but not limited to, cationic salts based on alkali metals and alkaline earth metals, for example, sodium salts, clock salts, potassium salts, dance salts, salt salts, salt salts, and climbing; and non-toxic, quaternary amines and amine cations, including However, it is not limited to ammonium, tetradecylammonium, tetraethylammonium, mercaptoamine, dimethylamine, tridecylamine monoethylamine, ethylamine, and the like, and can be used for other representative formation of alkali addition salts. The organic amines include diethylamine, ethylenediamine, ethanolamine, diethanolamine, miso, and the like. The term "pharmaceutically acceptable prodrug" as used herein refers to the prodrugs of the compounds of the present invention which are reliable. Medical judgment within the scope of • contact with humans and lower animals and will not produce Excessive toxicity, irritation, allergic reaction, and the like, and commensurate with a reasonable benefit/risk ratio and effective for its intended use, and may also refer to the zwitterionic form of the compound of the present invention. The term "prodrug" means For example, a compound that produces a parent compound of the above formula, for example, vinegar, by rapid hydrolysis in the blood. A comprehensive discussion is provided by Higuchi, T. and V. Stella, "Prodrugs as Novel Delivery Systems" (ACS Symposium Series). 14) and "Bioreversible Carriers in Drug Design" edited by Edward B. Roche (American Pharmaceutical 144363.doc •27· 201032806

In Association, Pergamon Press, 1987), both are incorporated herein by reference. In various embodiments, the pharmaceutical compositions of the present invention comprise a first pharmaceutical component and a second pharmaceutical component in a pharmaceutically acceptable carrier. The first component of the compound of formula (1)

Ra Ο

Or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof, wherein

Ra is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) CVC6 alkoxy, (5) mercaptan, (6) CVC6 alkyl mercaptan, (7) substituted Or unsubstituted C^-Ce alkyl, (8) amino or substituted amine, (9) substituted or unsubstituted aryl, (10) substituted or unsubstituted heteroaryl, and 144363. Doc -28- 201032806 (π) substituted or unsubstituted heterocyclic group; R is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted Ci_C6 alkyl, (3) Substituted or unsubstituted C2-C6 alkenyl, (4) substituted or unsubstituted C2-C6 alkynyl, (5) substituted or unsubstituted c3_c^^ alkyl, (6) substituted or not Substituting (^-.cycloalkenyl, ® (7) substituted or unsubstituted aryl, (8) substituted or unsubstituted heteroaryl, and (9) substituted or unsubstituted heterocyclic;

Rb is selected from the group consisting of: (1) substituted or unsubstituted C3_C7 cycloalkyl, (2) substituted or unsubstituted C5_c7 cycloalkenyl, (3) substituted or unsubstituted aryl, _ (4) a substituted or unsubstituted heteroaryl group, and (5) a substituted or unsubstituted heterocyclic group; and the limitation is that if Ra is an amine group, Rb is not a phenyl group, a 4-alkyl-benzene group 'Base, 4-alkoxy-phenyl, or 4-complex stupid. • This second component is an mTOR inhibitor. Preferably, the first component is an HsP 90 inhibitor. In a particular embodiment, the first component of the compound of formula (IV) 144363.doc •29· 201032806

Ra η

(la) or a tautomer thereof, a pharmaceutically acceptable salt, or a prodrug wherein the base 'n' is not phenyl, 4' alkyl-styl, 4-alkoxy-stirty, or 4_ Halophenyl. In certain embodiments of the compounds of formula (I) or (la), Ra is hydrogen. In other embodiments, Ra is substituted or unsubstituted Cl-C6 alkyl. In certain embodiments, mCl_C6 is alkyl or deuterated Ci_C6 alkyl. In some of these embodiments, Ra is a fluorenyl group. In certain embodiments the 'W is an aryl or heteroaryl group. In certain such embodiments, Rb is selected from the group consisting of phenyl...(tetra), thio, m, thiazolyl, and thienyl, each of which may be substituted or unsubstituted. In some aspects, the invention provides compounds wherein the above oxime group is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In other aspects, the Rb groups can be substituted via a functional group. In other aspects, the groups can be substituted with fluorine. In still other aspects, the Rb groups can be substituted with an alkyl group, a haloalkyl group, an alkoxy group, and a haloalkoxy group. In some aspects, the Rb groups can be substituted with a methyl group. In other aspects, the Rb groups may be substituted with a methoxy group. In other embodiments, Rb is selected from the group consisting of substituted aryl, substituted heterocyclic 144363.doc 201032806, substituted heteroaryl, substituted Cs-C7 cycloalkyl, and _ 5 _ L 7 cycloalkenyl The group of the composition 'wherein the aryl group, the heterocyclic group, the heteroaryl group, the 13-membered 7-ring group and the Cs-C7 cycloalkenyl group are selected from the group consisting of n-rho groups, stupid groups, ° ratios , thiol, sulfonyl, oxazinyl, D is more than salivary, taste. Sodium, triazolyl, sulfhydryl, oxadiazolyl, thiadiazolyl'furanyl, quinalinyl, isoindolyl, oxonyl, beta oxo, 嚷β , morphinyl, hexahydropyridyl, pyrrolidinyl, thienyl, cyclohexyl, cyclopentyl, cyclohexyl and cyclopentenyl. In some aspects, the above groups may be through i to 2 Substituent substitution of a group consisting of a free halo group, an alkoxy group, an alkyl group, an amine group, an alkylamino group, a haloalkyl group, and a haloalkoxy group. In certain embodiments, the R system is selected from the group consisting of hydrogen and a group consisting of a substituted alkyl group and a substituted alkyl group. In some of these embodiments, R is selected from the group consisting of methyl, ethyl, allyl, 3-methyl-butyl, and isobutyl. In other embodiments 'R is selected from the group consisting of hydrogen, benzyl, 1-(4-methoxyphenyl)ethyl, methyl, 3-aminopropyl, and 2-methyl-2-morpholinyl A group of propyl groups. In yet another embodiment, R is hydrogen. In another embodiment, the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidine- The 5-ketone compound has the formula (II):

Ra 〇

• 31· 144363.doc 201032806 A pharmaceutically acceptable salt, or a stereoisomer or tautomer thereof, wherein η is 0 or 1, wherein the Ra is selected from the group consisting of: (1) hydrogen , (2) halogen, (3) hydroxyl, (4) CVC6 alkoxy, (5) mercaptan, (6) Ci-C^alkyl mercaptan, (7) substituted or unsubstituted CiC6 alkyl, (8) an amine group or a substituted amine group, (9) a substituted or unsubstituted aryl group, (10) a substituted or unsubstituted heteroaryl group, and (11) a substituted or unsubstituted heterocyclic group; Wherein R is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted C1-C6 alkyl, (3) substituted or unsubstituted c2_C6 alkenyl, (4) substituted or unsubstituted c2_C6 alkyne Substituted, (5) substituted or unsubstituted - alkyl, (6) substituted or unsubstituted - alkenyl, (7) substituted or unsubstituted aryl, (8) substituted or unsubstituted Aryl, and 144363.doc -32- 201032806 (9) substituted or unsubstituted heterocyclic group, wherein when field 11 is 1, X is C, and γ at each position is independently selected from CQ and hydrazine, and ΖSelected from CR2 and Ν, the restriction is not exceeded After 3 γ& ζ groups are Ν, and where field 11 is 〇, X is C or Ν, γ at each position is independently selected from CQ N NQ, 〇 and s 'limitation is no more than 4 The 乂 and γ groups are Ν and NQ2 and no more than 1 γ group is s or 〇; wherein qi at each position is independently selected from the group consisting of: • (1) hydrogen, (2) halogen, (3) Substituted or unsubstituted Ci_c6 alkyl, (4) substituted or unsubstituted c2_C6 alkenyl, (5) substituted or unsubstituted C2_C6 alkynyl, (6) substituted or unsubstituted (:3_( :7 cycloalkyl, (7) substituted or unsubstituted c5_C7 cycloalkenyl, (8) substituted or unsubstituted aryl, ® (9) substituted or unsubstituted heteroaryl, (10) Substituted or unsubstituted heterocyclic group, (1丨) substituted or unsubstituted amino group, (12) -OR3 or -SR3, (13) -C(0)R3, _c〇2R3, -C(0) N(R3)2, -S(0)R3, -S〇2R3, or -so2n(r3)2, (14) -〇C(0)R3, _n(R3)C(〇)R3, or -N (R3) S02R3, (15) -CN, and 144363.doc •33· 201032806 (16) -N〇2 ; wherein each position Q2 is independently selected from the group consisting of: (1) hydrogen, ( 3) substituted or unsubstituted c]-c6 alkyl, (4) substituted or unsubstituted c2_c6 alkenyl, (5) substituted or unsubstituted c2_c6 alkynyl, (6) substituted or unsubstituted C3_c7 cycloalkyl, (7) substituted or unsubstituted c5_c7 cycloalkenyl, (8) substituted or unsubstituted aryl, (9) substituted or unsubstituted heteroaryl, and (10) substituted Or an unsubstituted heterocyclic group; wherein R2 is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) substituted or unsubstituted C1-C3 alkyl, and (4) _〇R3, -SR3 or -NHR3; wherein, each position R3 is independently selected from the group consisting of (1) hydrogen, (2) substituted or unsubstituted C1-C6 alkyl, (3) substituted or unsubstituted c2_C6 alkenyl, (4) Substituted or unsubstituted c2_C6 alkynyl, (5) substituted or unsubstituted alkyl, (6) substituted or unsubstituted c5_C7 cycloalkenyl, (7) substituted or unsubstituted aryl, 144363 .doc •34- 201032806 (8) Substituted or unsubstituted heteroaryl, and (9) substituted or unsubstituted heterocyclic group, with the proviso that if Ra is an amine group, then χ, γ, 2 and n Benzene cannot be formed together Base, 4-alkyl-phenyl, 4-alkoxy-phenyl or 4-phenylene. In other embodiments, the first pharmaceutical component of the invention is based on formula (Ha):

Ra 〇

Or a tautomer thereof, a pharmaceutically acceptable salt, or a prodrug, wherein Ra, R, X, oxime, z, and n are as defined previously for formula (11) and the restriction is if Ra is an amine Further, X, γ, 2 and η together cannot form a phenyl group, a 4-alkyl-phenyl group, a 4-alkoxy-phenyl group, or a 4-carboxylphenyl group. ❹ In some embodiments, if η is 〇, then X is c and 临近 is not Ο. In certain embodiments of the compound of formula (II) or (Ila), Ra is hydrogen. In other embodiments, Ra is a substituted or unsubstituted Cl_c6 alkyl group. In certain embodiments, 1 is alkyl or haloalkyl. In certain such embodiments, Ra is a methyl group. For the compounds of formula (I), (la), (II) or (Ha), representative substituted alkyl groups include arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclyl I44363 .doc .35- 201032806 Alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, and sulfonylamino. Representative aryl groups include phenyl. Representative heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, indolyl, quinolyl, isoquinolinyl, furyl, oxazolyl, thiazolyl, and thienyl. In one embodiment, a Q1 or Q2 is selected from the group consisting of substituted and unsubstituted phenyl, substituted and unsubstituted pyridyl, substituted and unsubstituted butyl, substituted, and Unsubstituted "pyrazinyl, substituted and unsubstituted fluorenyl, substituted and unsubstituted thiazolyl, and substituted and unsubstituted thienyl. In one embodiment, a Q1 or Q2 is selected from the group consisting of hexahydropyridyl 'morphine, pyrrolidinyl and benzylamine. In one embodiment, a Q1 or Q2 is selected from the group consisting of cyclohexyl and cyclopentyl. In one embodiment, a Q1 or Q2 is selected from the group consisting of cyclohexenyl and cyclopentenyl. In one embodiment, a Ql or Q2 is selected from the group consisting of substituted aryl, substituted heterocyclic, substituted heteroaryl, substituted C3_C7 cycloalkyl, and substituted C5-C./cycloalkenyl. a group wherein the aryl group, heterocyclic group, heteroaryl group, Cs-C:7 cycloalkyl group and C5_C7 cycloalkenyl group are selected from the group consisting of: 11 phenyl, phenyl, pyridyl, pyrazinyl , pyrimidinyl, pyridazinyl, pyrazolyl, pyridyl, triazolyl, fluorenyl, oxadiazolyl, thiadiazolyl, furyl, quinalyl, isoindolyl, heterosexual Base, oxalyl, thiazolyl, 144363.doc 201032806 morpholinyl, hexahydropyridyl, pyrrolidinyl, thienyl, cyclohexyl, cyclopentyl, cyclohexenyl and cyclopentenyl. In some aspects, the above groups may be formed from 1 to 2 groups selected from the group consisting of i, alkoxy, alkyl, amine, alkylamino, southern alkyl and dentate alkoxy groups. Substituted by a group of substituents. In one embodiment, a Q1 or Q2 is selected from substituted and unsubstituted pyridyl, substituted and unsubstituted pyrazinyl, substituted and unsubstituted phenyl, substituted and unsubstituted Isoquinolinyl, substituted and unsubstituted pyrimidine® groups, substituted and unsubstituted pyrazolyl groups, and substituted and unsubstituted furyl groups. In some aspects, the above group may be substituted with one to two substituents selected from the group consisting of a functional group, an alkoxy group, an alkyl group, an amine group, an alkylamino group, a halogenated alkyl group, and a halogenated alkoxy group. . In other embodiments, a Q1 or Q2 is selected from the group consisting of: (2-hydroxy-ethylamino)-pyrazine-2-yl, 1H-pyrazol-4-yl, 1-indenyl- 1H- 吼. -4-yl, 1-methyl-1H-pyrazol-4-yl, 2-(5-methyl-pyridin-2-yl)-phenyl, 2,3-difluoro-phenyl, 2, 3-dimethoxy-phenyl, 2,4-difluoro-phenylφ, 2,4-dimethoxy-phenyl, 2,4-dimethoxyoxy-pyrimidin-5-yl, 2, 5-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dimethyl-pyridin-3-yl, 2-ethylaminophenyl, 2-aminocarbonylphenyl, 2 -Amino-pyrimidin-5-yl, 2-chloro-4-.decyloxy-pyrimidin-5-yl, 2-a-5-fluoro-pyridin-3-yl, 2-a-phenyl, 2- Chloridin-3-yl, 2_gas-"bipyridin-4-yl, 2-difluoro-3-indolylphenyl, 2-ethyl-phenyl, 2-ethoxy-thiazole-4 -yl, 2-fluoro-3-methoxy-phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-mercapto-phenyl, 2-fluoro-5-methoxy-benzene , 2-fluoro-5-fluorenylphenyl, 2-fluorophenyl, 2-fluoro-n-bipyridyl-3-yl, 2-hydroxymethyl 144363.doc -37- 201032806 -3--3-methoxybenzene , 2-hydroxymethylphenyl, 2-isoquinolin-4-yl, 2-methoxy-5-trifluorodecyl-phenyl, 2-decyloxy-phenyl, 2-indenyl - acridine-3-yl, 2-methoxy-pyrimidin-4-yl, 2-decyloxy-thiazol-4-yl, 2-mercapto-phenyl, 2-methyl-pyridin-3-yl 2-sided oxygen -1,2-dihydro-pyridin-3-yl, 2-phenoxyphenyl, 2-. Bis-1-yl, 2-pyrimidin-5-yl, 2-trifluoromethoxyphenyl, 2-trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, 3, 5-dimethyl 'isoxep-4-yl, 3,6-dimercapto-° ratio C-Qin-2-yl, 3-ethylamine basic, 3-aminophenyl, 3- >Smelly-phenyl, 3·Chloro-17 to 17-Qin-2-yl, 3-Champylphenyl, 3-D-decylaminophenyl, 3-ethoxy-phenyl, 3-ethyl -4 -Methyl-phenyl, 3-ethylhexyl-phenyl, 3- gas-6-decyloxy-. Than-2-yl, 3-(phenylene), 3-fluoro/pyrazin-2-yl, 3-methanesulfonylaminophenyl, 3-decyloxycarbonylphenyl, 3-methoxyphenyl , 3-decyloxy-pyridazin-2-yl, 3-mercapto-3Η-imidazo[4,5-b]pyrazin-5-yl, 3-methylphenyl, 3-methyl-pyridine 2-yl, 3-trifluoromethoxyphenyl, 3·trifluoromethylphenyl, 4,5-dimethoxyoxy-mouth-2-yl, 4-amino-5-fluoro-. Cyclodecyl-2-yl, 4- gas-2,5-dimethoxy-phenyl, 4-chloro-2- gas-phenyl, 4-air-2-methoxy-5-fluorenyl- Phenyl, 4-oxo-indole is more than -3-yl, 4-dioxa-2-indenyl-phenyl, 4-ethoxy-5-chaotic-feeding. Ding-2-yl, 4-ethoxy-y-ylide-2-yl, 4-ethylidyl-nodyl-5-yl, 4-ethyl-1H-indazol-3-yl, 4-fluoro- 2-decyloxy-phenyl, 4-fluoro-2-methyl-phenyl, 4-p-phenyl, 4-mercapto-5-methyl- whistling. -2-2-yl, 4-methyllacyl-σ 唆-3 _ group, 4-methoxy pyrimidin-2-yl, 4-decyloxy-pyrimidin-5-yl, 4·decyl-phenyl , 4 · methyl-σ ratio bit-2-yl, 4 · thiol-17 ratio biting _ - 3 - group, 4 - σ ratio 11 -1 -yl-pyrimidin-2-yl, 5,6-di Methoxypyrazin-2-yl, 5-ethenyl-thiophen-2-yl, 5-amino-6-ethoxy-pyrazin-2-yl, 5-amino-6-methoxy Base-3-曱144363.doc -38- 201032806 base-0 to indole-2-yl, 5-amino-6-methoxy-D than bit-2-yl, 5-a-4-pyridyloxy -pyrimidin-2-yl, 5-gas-6-decyloxy-pyrazin-2-yl, 5-didecylamino-6-methoxy-π ratio β桊_2-yl, 5-fluoro -2-methoxyphenyl, 5, _4·methoxy- 啸 -2--2-yl, 5-fluoro-6-methoxy-11 ratio ° Qin-2-yl, 5-gas-π Specific bite_2_yl, 5-methoxy-π ratio _3-yl, 5-methoxy-porphin-2-yl, 5-trifluoromethyl_mouth-2-yl, 6_ Ethyl-I»Bis-2-yl, 6-chloro-" bis-2-yl, 6-ethoxy-π 嘻·2_yl, 6-ethoxy ratio 0^-2 - base, 6-span ratio bite_2_yl, 6-fluoropyridin-3-yl, 6-severyl ratio bit-2-yl, 6-methoxy-5.methylamino group _ ° 嗓 - 2-based, 6-methoxy-5-mercapto-0 More than indol-2-yl, 6-methoxy-oxime 0-2-yl, 6-methoxy-oxime ratio -2-yl, 6-decyloxy-oxime ratio. Benz-3-yl, 6-methylamino group ° Qin-2-yl, 6-fluorenyl nib-2-yl, 5-amino-6-(2,2,2-trifluoroethoxy π is more than 嘻_2-based, and 6-di-deuterogenyl-0 is more than -2-. In one embodiment, Q1 is halo. In one embodiment, Q1 is an alkyl group. In some aspects, qi is a methyl group. In one embodiment, R2 is selected from the group consisting of hydrogen and fluorine. In some aspects, R2 is fluorine. In one embodiment, R2 is selected from the group consisting of alkyl groups. In some aspects, R2 is methyl. In one embodiment, R2 is selected from alkoxy. In some aspects, R2 is methoxy. In one embodiment, Q1 is 〇R3. In one embodiment, 'R3' is selected from the group consisting of methyl, ethyl, isopropyl, cyclopentyl and cyclohexyl. 144363.doc •39- 201032806 In one embodiment 'R3 is selected from substituted and unsubstituted phenyl, substituted and unsubstituted thiazolyl, substituted and unsubstituted pyridyl, substituted and unsubstituted Pyrazinyl and substituted and unsubstituted pyrimidinyl. In one embodiment, R3 is selected from the group consisting of 2-aminoethyl, 2-hexahydropyridylethyl, 2-piperazinyl '2-morpholinylethyl, and 2-(N-methylpiperazine) a group of ethyl groups. In certain embodiments, the 'R is selected from the group consisting of hydrogen, unsubstituted alkyl, and substituted theater groups. In certain such embodiments, r is selected from the group consisting of methyl, ethyl, allyl, "yl-butyl, and isobutyl." In other embodiments, R is selected from the group consisting of hydrogen and a sulfhydryl group. , κ (4-methoxyphenyl) ethyl, methyl, 3-aminopropyl, and 2-methylamino 9-malinylpropyl. In another embodiment of the present invention A two component mTOR inhibitor combination is provided as the first component and as a compound of formula (III):

Ra π

R8 R5 A pharmaceutically acceptable salt, or a stereoisomer, tautomer, prodrug thereof, wherein 144363.doc 201032806 wherein ... is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) ) hydroxy, (4) alkoxy, - (5) thiol, (6) G-C6 alkyl thiol, (7) substituted or unsubstituted Ci_C6 alkyl, Φ (8) amine or substituted Amino, (9) substituted or unsubstituted aryl, (10) substituted or unsubstituted heteroaryl and (11) substituted or unsubstituted heterocyclic; V is hydrogen or substituted or not Substituting Ci_c6 alkyl; S is hydrogen, alkyl, alkoxy, or dentate; R, R, R8 and R9 are each independently selected from hydrogen, alkyl, alkoxy, fluorenyl, substituted or Unsubstituted aryl, and substituted or unsubstituted heterocyclic groups; or - their isomers, tautomers, pharmaceutically acceptable salts, or pre-[5] If R is an amine group and R6, R7, R8 and R9 are hydrogen, then • R may not be hydrogen, an alkyl group, an alkoxy group, or a substituent. ^ In the examples, the formula (1)(4) is provided as the first component. I44363.doc -41 - 201032806

Or a tautomer thereof, a pharmaceutically acceptable salt, or a prodrug thereof, wherein Ra ' R4 ' r5 ' R6, R7, R8 and R9 are as defined above for formula (III) and the restriction is 1^ Is an amine group and R6, R7, R8 and R9 are nitrogen, and R5 is not hydrogen, alkyl, alkoxy, or a dentate group. In certain embodiments, Ra is hydrogen. In certain embodiments, Ra is substituted or unsubstituted Ci_c6 alkyl. In certain embodiments, 1 is a Cl_c6 alkyl group or a halogenated Cl_c6 alkyl group. In some of these embodiments, Ra is a fluorenyl group. In certain embodiments of the invention, R4 is selected from the group consisting of hydrogen, benzyl, methoxyphenyl)ethyl, decyl, 3-aminopropyl, and 2-indenyl-2-morpholinopropyl Group. In other embodiments, R is selected from the group consisting of decyl, ethyl, propyl, 3-decyl-butyl, and isobutyl. In certain embodiments, R5 is hydrogen or fluoro. In some aspects, the ruler 5 is fluorine. In certain embodiments, R5 is methyl or methoxy. In certain embodiments, each of R7, R8, and R9 is hydrogen. In certain embodiments, 'R6 is exemplified by 1 to 2 selected from halo, alkoxy 144363.doc • 42· 201032806, alkyl, amine, alkylamine, alkenyl, and haloalkoxy An aryl or heteroaryl group substituted with a substituent of the group of base groups. In certain embodiments, R6 is selected from the group consisting of substituted aryl and substituted heteroaryl, wherein the aryl and heteroaryl are selected from the group consisting of furanyl, fluorenyl, phenyl , pyridyl, pyridazinyl, pyrimidinyl, thiazinyl, pyrazolyl, imidazolyl, triazolyl, fluorenyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, iso Oxazolyl, oxazolyl, thiazolyl, and porphinyl. In some aspects, the above group may be one or two selected from the group consisting of a haloalkyl alkoxy group, an alkyl group, an amine group, an alkylamino group, a dentate alkyl group, and a halogenated alkoxy group. Substituent substitution. In other embodiments, R6 is selected from the group consisting of: (2-trans-ethylamino)-pyridyl-2-yl, 1H- 0 to 0--4-yl, 1-indenyl-i H- ° is 0-base-4, methyl-1Η-»比峻-4-yl, 2-(5-fluorenyl-η ratio bit_2_yl)-phenyl, 2,3--I- Phenyl, 2,3-dimethoxy-phenyl, 2,4-difluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-pyrimidine-5- , 2,5-difluoro-phenyl, 2,6-di-n-phenyl, 2,6-dimethyl-pyridin-3-yl, 2-ethylaminophenyl, 2-amine Alkyl phenyl, 2-amino group, mouth bite-5-yl, 2-gas_4_methoxy-pyrimidin-5-yl, 2·gas-5-fluoro-pyridin-3-yl, 2- Gas-phenyl, 2-chloro-pyridine-3-yl, 2-chloro.bipyridyl-4-yl, 2-difluoro-3-indolyl, 2-ethyl-phenyl, 2- Ethoxy-thiazole-4-yl, 2-fluoro-3-yloxy-phenyl, 2-fluoro-4-methylphenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro 5_曱oxy_styl, 2_fluoro_5_ 曱 basic, 2-fluorophenyl, 2-fluoropyridyl-3-yl, 2-pyridylmethyl-3-methoxyphenyl, 2 -hydroxymethylphenyl, 2-ioquinoline-4-yl, 2-methoxycarbonyl_5-trifluoromethyl-phenyl, 2-methoxy-phenyl, 2_ Oxyl „ 比 · 3 3 2, 2 144363.doc -43 - 201032806 methoxy-pyrimidin-4-yl, 2-decyloxy-thiazol-4-yl, 2-mercapto-phenyl, 2- Methyl-ϋ 咬 -3 · · 、 2 2 2 2 2 -3 · · · · · · · · · · · · · · 2 2 2 2 2 2 2 2 2 2 2 2 2 2 -pyrimidin-5-yl, 2-trifluoromethoxyphenyl, 2-trifluorodecyloxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-didecyl-iso- Azole 4-yl, 3,6-dimercapto-pyrazin-2-yl, 3-ethylamidophenyl, 3-aminodylphenyl, 3 -> odor-phenyl, 3- Scrambled-2 -yl, 3-butenylphenyl, 3·didecylaminophenyl, 3-ethoxy-phenyl, 3-ethyl-4-indolyl-phenyl, 3-B Fast-phenyl, 3- gas-6·methoxy-σ-pyridin-2-yl, 3- gas phenyl, 3·fluoro-pyridazin-2-yl, 3-decanesulfonylaminobenzene ,3,methoxycarbonylphenyl, 3-methoxyphenyl, 3-methoxy-pyridazin-2-yl, 3-methyl-3-indole-imidazo[4,5-b]pyrazine -5-yl, 3-methylphenyl, 3-mercapto-pyridin-2-yl, 3-trifluoromethoxyphenyl, 3-trifluoromethylphenyl '4,5-dimethoxy -pyrimidin-2-yl, 4-amino-5-a-furan-2-yl, 4-chloro-2,5-di Group - phenyl, 4-gas -2-- gas-phenyl, 4 - wind (2-milk-5 - methyl - group present, 4. Milk -.淀丁-3_yl, 4-di-2-yl-methyl-phenyl, 4-ethoxy-5-gas-nose sigma-2-yl, 4-ethoxy-azepine-2-yl , 4-ethoxy-17 succinyl-5-yl, 4-ethyl-1 Η - ° ratio σ sitting -3 yl, 4- gas-2-decyloxy-phenyl, 4- gas-2 - mercapto-phenyl, 4-p-phenyl, 4-mercapto-5-indenyl-dense-2 -yl, 4-methoxy-σ-precipitate-3-yl, 4-oxo Alkyl-pyrimidin-2-yl, 4-methoxy-pyrimidin-5-yl, 4-methyl-phenyl, 4-mercapto-β ratio. Determine _ 2 -base, 4-methyl-^ ratio. D--3, 4-α-pyrrol-1 -yl-mouth- 2 ·yl, 5,6-dioxalate-° ratio β-Qin-2-yl, 5-ethyl-bristyl-porphin-2 -yl, 5-amino-6-ethoxy_σ ratio °Qin-2-yl, 5-amino-6-methoxy-3-methyl-σ -2-2-yl, 5-amine Base-6-methoxy-. ratio. -2 -yl, 5-oxo-4-methoxy- ̄3⁄4-precipitate 2-yl, 5- gas-6-decyloxy-0-but-2-yl, 5-dimethylamino- 6-decyloxy-σ ratio 144363.doc •44- 201032806 °Qin-2-yl, 5-fluoro-2-methoxyphenyl, 5-fluoro-4-indolyl-branch-2-yl , 5-fluoro-6-decyloxy-pyrazin-2-yl, 5-fluoro-pyridin-2-yl, 5-methoxy-pyridyl-3-yl, 5-methoxy-porphin- 2-based, 5-dione fluorenyl-β-bense-2-based, 6 _ ethyl-branched-° ratio -2, base- 6-milk-° ratio ° Qin-2-based, 6-B Oxy-α is more than π-Qin-2-yl, 6-ethyllacyl-ntb.定-2 - base, 6 - gas-0 ratio bite - 2 - base, 6 - gas - π ratio bite - 3 - base, 6 - light base - π ratio bite - 2 - base, 6 - methoxy-5 -Methylamino-α-pyridin-2-yl, 6-methoxy-5-methyl-pyrazin-2-yl, 6-methoxy-pyrazin-2-yl, 6-decyloxy -π is more than 唆-2 -yl, 6-decyloxy-° ratio. 3-decyl, 6-fluorenylamino-0-pyridyl-2, benzyl, 6-methyl-pyridin-2-yl, 5-amino-6-(2,2,2-trifluoroethyl Oxy)pyrazin-2-yl, and 6-trifluorodecyl-pyridin-2-yl. The first component and the second component of the pharmaceutically acceptable carrier can be provided to form a pharmaceutical composition. In another embodiment of the invention, a compound of formula (IV) is provided as the first component:

(IV) or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof, wherein R4 is hydrogen or substituted or unsubstituted CkG alkyl, 144363.doc -45 - 201032806 R is The hydrogen or halo group » 6a R a is selected from the group consisting of halo, M, 'or substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In certain embodiments, a compound of formula (IVa) is provided as a first component for the first component:

(IVa) or a tautomer thereof, a pharmaceutically acceptable salt, or a prodrug thereof, wherein R4, R5 and R6a are as defined above for formula (IV). In certain embodiments of the compound of Formula (IV) or (IVa), R4 is selected from the group consisting of hydrogen, benzyl, hydrazine 'methoxyphenyl) ethyl, methyl, 3-aminopropyl, and a group consisting of -methyl-2-yl-propyl. In other embodiments, R is selected from the group consisting of methyl, ethyl, allyl '3-mercapto-butyl, and isobutyl. In certain embodiments 'R5 is hydrogen or fluorine. In some aspects, r5 is fluorine. In certain aspects, R6a is a group consisting of 1 to 2 selected from the group consisting of halo, alkoxy, alkyl, amine, alkylamine, hydrazino, and alkoxy. Substituent substituted aryl or heteroaryl. 144363.doc -46 - 201032806 In certain embodiments 'R6a is selected from the group consisting of substituted aryl and substituted heteroaryl, wherein the aryl and heteroaryl are selected from the group consisting of: cough Base, η than succinyl, phenyl, oxime, ^ 嗓 、, mouth bite, ° azine base, "ratio. Sodium, imidazolyl, triazolyl, indolyl, oxadiazolyl, di-saltyl, quinolyl, isoquinolyl, isoxazolyl, oxazolyl, thiazolyl and anthranyl. In some aspects, the above group may be one or two selected from the group consisting of a functional group, an alkoxy group, an alkyl group, an amine group, an alkylamino group, a functional alkyl group, and a halogenated alkoxy group. Substituent substitution. In certain embodiments, the ruler 62 is selected from the group consisting of: (2-hydroxy-ethylamino)-°-but-2-yl, 1 Η-° ratio. -4-yl, 1-methyl-1Η-"比嗤_4_ base, 1-mercapto-1Η-» ratio" sit-4-yl, 2-(5-methyl ratio bite-2- Phenyl, 2,3-difluoro-phenyl, 2,3-dimethoxy-phenyl, 2,4-difluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-pyrimidin-5-yl, 2,5-difluoro-phenyl, 2,6-difluoro-styl, 2,6-diinyl than -3-yl, 2 -Ethylaminophenyl, 2-aminophenylphenyl, 2-amino-[3⁄4]-5-yl, 2-air-4-decyloxy- ♦Bite-5-yl, 2-chloro -5-gas-D ratio bit-3-yl, 2- gas-phenyl, 2- gas-purine-3-yl, 2-gas-pyridin-4-yl, 2-difluoro-3-methoxy Phenyl, 2-ethyl-phenyl, 2-ethoxy-°°-4-yl, 2-ox-3-methoxy-phenyl, 2-ox-3-methylphenyl , 2-fluoro-4-methyl-phenyl, 2-fluoro-5-decyloxy-phenyl, 2-fluoro-5-nonylphenyl, 2-fluorophenyl, 2-fluorobipyridine-3- , 2-hydroxymethyl-3-methoxyphenyl, 2-hydroxymethylphenyl, 2-isoquinolin-4-yl, 2-decyloxy-5-trifluoromethyl-phenyl, 2-methoxy-phenyl, 2-methoxy-D-pyridyl-3-yl, 2-methoxy-pyrimidin-4-yl, 2-decyloxy-thiazol-4-yl, 2-methyl -phenyl, 2-methyl -pyridine-3-yl, 2-oxo-1,2-dihydro-pyridin-3-yl, 2-phenoxy 144363.doc -47- 201032806 Phenyl, 2-pyrid-3-yl, 2 -pyrimidin-5-yl, 2-trifluoromethoxyphenyl, 2-trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethyl-isoan Squatting -4 -yl, 3,6-dimethyl-° ratio, Qin-2-yl, 3-ethylaminophenyl, 3-aminocarbylphenyl, 3 -> odor-phenyl , 3 -milk-σ than 嗓-2-yl, 3-disorganylphenyl, 3·dimethylaminophenyl, 3-ethoxy-phenyl, 3-ethyl-4-indenyl-benzene Base, 3-ethylidene-phenyl, 3- gas-6-methoxy-° ratio. Dec-2-yl, 3-oxophenyl, 3-fluoro-pyridazin-2-yl, 3-decanesulfonylaminophenyl, 3-methoxycarbonylphenyl, 3-decyloxyphenyl , 3-decyloxypyrazine-2-yl, 3-methyl-3-indole-imidazo[4,5-b]pyrazin-5-yl, 3-nonylphenyl, 3-methyl-pyridine- 2-Based, 3-trifluorodecyloxyphenyl, 3-trifluorodecylphenyl, 4,5-dimethoxyoxy-pyrimidin-2-yl, 4-amino-5-gas-tight sigma- 2-Based, 4-Gas-2,5-dimethyllacyl-phenyl, 4-Ga-2-on-phenyl, 4-Gas-2-methoxy-5-methyl-phenyl, 4 - gas-° ratio bite - 3-yl, 4-dioxa-2-methyl-phenyl, 4-ethyllacyl-5-gas·napon-2-yl, 4-ethoxy-pyrimidine-2 -yl, 4-ethoxy-pyrimidin-5-yl, 4-ethyl-1 fluorene-pyrazol-3-yl, 4-fluoro-2-indolyl-phenyl, 4-ox-2-yl -phenyl, 4-oxophenyl, 4-methoxy-5-methyl-pyrimidin-2-yl, 4-methoxy-pyridin-3-yl, 4-decyloxy-pyrimidin-2-yl 4-methoxy-pyrimidin-5-yl, 4-methyl-phenyl, 4·fluorenyl-° than 2-hydroxy-2-yl, 4-methyl-σΐΐί- 3 -yl, 4 -loxidine -1 -yl-manganese-2 -yl, 5,6 -dimethoxy-^,2 -yl, 5-ethoxyphenyl-dexoster-2-yl, 5-amino-6 Oxy-17 is more than 2-yl, 5-amino-6-methoxy-3-methyl-° ratio Qin-2 _ group, 5-amino-6-methyllacyl-D ratio -2-yl, 5-lactic-4-methoxy-precipitate-2-yl, 5-chloro-6-decyloxypyridin-2-yl, 5-dimethylamino-6-methoxy -2--2-yl, 5-a-2-nonyloxyphenyl, 5-a-4-pyridyloxy-°3⁄4唆-2-yl, 5-fluoro-6-methoxy-pyridazine- 2-yl, 5-fluoro-acridin-2-yl, 5-methoxy-pyridyl 144363.doc -48- 201032806 -3--3-yl, 5-methoxy-porphinyl-2-yl, 5_ Trifluoromethyl-mouth 々··,6 醯 比 咬 咬 I, 6 1 嗪 嗪 6 6 6 6 6 6 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙, heart fluorine-pyridine-2-yl, 6-fluoro-〇 also ★ 3, 6-hydroxypyridin-2-yl, 6-methoxy-5-methylamino-pyrazine, h-based, 6 ·Methoxy-5-methylpyrazine-2-yl, 6-methoxyl oxime-2-yl, phenylmethylpyridin-2-yl, 6-methoxy-pyridine-3-yl , 6-methylamino-pyrazine <yl, 6-methyl" is more than 2-amino, 5-amino, 2,2,2, triethoxyethoxy 2, and 6 -Trifluoromethyl-pyridin-2-yl. The compound of the present invention comprises: a preferred Hsp9 oxime inhibitor for use in the first component () 2-amino-7-[2-(2-l-n-bipyridyl-3-yl)phenyl]·4 methyl & Dihydro-6Η-pyrido[4,3_d]pyrimidin-5one oxime, —Amino-6·] _7_“4 & Field hamster 2'2-fluoropyridin-3-yl) -phenyl]_4· -7,8-dihydro-6Η_pyrido[43d]pyrimidin-5one; Amino-7·[4-Gas _ > -Fluorum ratio _3_ base) - stupid base]-4-methyl_,-monooxy-6Η-pyrido[4,3_d]pyrimidine_5__ ; (Hhenylamino-7(2_ 淳-4- ϋ ^ (... Amino-Homesick) ^ 7〇_ . 1 Rolling base _° than pyridine 2_ kib stupid base] -4- 曱 beautiful, one oxygen 1 〇 than bite and [4, 3 brother bite 5-ketone; soil (R) ~ 2-Amino-7-[4-fluoro-2-(6-indole A7R^milyl ratio _2~yl)-phenyl]-4-methyl,8.dihydro-6H" And [4,3-bite _5-ketone; 2_amino-7-[4-fluoro-2-(6-methyl-yl-78-oxy-.pyridin-2-yl)' stupyl -4,6-diindole, 8--indole-6H-pyrido[4,3-d]pyrimidin-5-one; 144363.doc -49. 201032806 2 -amino-7-[4-fluoro-2- (2-Oxo-0-indol-3-yl)-phenyl]-4,6-dimethyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; 2-amine -7-[4-fluoro-2-(6-methoxy)pyridin-2-yl)phenyl]-4-methyl-7,8-dihydro D ratio bite [4,3-(1 Mouth. Ding-5(6H)-one; 2-amino-7-[2-(6-methoxy-0-pyridin-2-yl)-phenyl]-4-methyl-7,8 -Dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; (R)-2-Amino-7-[4- disorder- 2- (6-methoxy-D vs. 0 Qin -2-yl)-benzyl]-4-mercapto-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; 2-amino--7- [4-disorder -2-(6-decyloxy-0-purin-2-yl)-phenyl]-4,6-dimercapto-7,8-dihydro-6-pyridyl[4,3-(1 Pyrimidine-5-one; 2-amino-7-[2-(2-methoxy-0-buty-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H -pyrido[4,3-d]pyrimidin-5-one; 2-amino-7-(5,2^ di-biphenyl-2-yl)-4-methyl-7,8-diaza -pyrido[4,3-d]pyrimidin-5-one; 2-amino- 7-(5-gas-21-trisethoxy-biphenyl-2-yl)-4-methyl-7 , 8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; 2-amino-7-[2-(2-gas-1? ratio -3-yl)-4- Gas-phenyl]-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; 2-amino--7- [4-morpho-2-( 6-gas-D ratio -3-yl)-phenyl]-4-methyl-7,8-dihydro-6Η-η ratio bite [4,3-d] Bite 5-ketone; 2-amino-7-(4-dis-2-ylindole-4-yl-phenyl)-4-indolyl-7,8-ifeng-6H-pyridyl[4 , 3-d]pyrimidin-5-one; 2-amino-7-(5,3l-disorder-biphenyl-2-yl)-4-mercapto-7,8-dipho-6H-0 ratio Bite and [4,3-d]°Bite-5-ketone; 144363.doc -50- 201032806 2-Amino- 7- [2-(4-milk-n ratio -3-yl)-4- Murine-phenyl]-4-methyl-7,8-dihydro-6Η-Π ratio bite [4,3-d] mouth bite 5-ketone; 2-amino group-7- (5,2· - Digas-3^methoxy-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-aitD deutero[4,3-d]°^. 5-amino-1-(5,4L difluoroi-2'-mercapto-biphenyl-2-yl)-4-methyl-7,8-dihydro-6Η-β More than bite [4,3-d] bite 5-ketone; 2-amino-7-(5-gas-21-methoxy-biphenyl-2-yl)-4-mercapto-7 8-Dinitrogen 611-11 is more than '1' [4,3-(1] mouth bite-5-one; 2-amino group - 7- (4- gas-2 - mouth °--5-yl- Phenyl)-4-methyl-7,8-diaza-6H-pyrido[4,3-d]pyrimidin-5-one; 2-amino-7-[4-fluoro-2-(2-曱oxypyridin-3-yl)-phenyl]-4-mercapto-7.8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; 2-amino--7- ( 5- gas-3'-methoxy-biphenyl-2-yl)-4-methyl-7,8-diaza-6Η-ΠΛ bite [4,3-(1]°3⁄4 bite-5- _ ; (R) _ 2 -amino- 6-(3-amino-propyl)-7-[4-gas-2-(6-methoxy-Dtb ate-2-yl)-phenyl] 4-methyl-7,8-dihydro-6H-.pyrido[4,3-d]pyrimidin-5-one; 2-amino-7-(4- gas-2-σ ratio bite- 3-yl-phenyl)-4-methyl-7,8-diazo-6H-pyrido[4,3-d]pyrimidin-5-one; 2-amino-7-(5,2'-di Fluoro-4·-methyl-biphenyl-2-yl)-4-mercapto-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; 2-amino group- 7- [4 - chaotic-2-(1-methyl-1Η-n ratio β sit-4-yl)-phenyl ]-4 -mercapto·7.8-dihydro-6Η-pyrido[4,3-d]pyrimidin-5-one; 2-amino-7-[4-fluoro-2-(111-°-by-azole- 4-yl)-phenyl]-4-methyl-7,8-di 144363.doc -51 - 201032806 Hydrogen-6H-pyrido[4,3-d]pyrimidin-5-one; 2-amino group- 4-methyl-7-(5,2,3'-trifluoro-biphenyl-2-yl)indole-8_dihydro-6h_pyrido[4,3-d]pyrimidin-5-one; 2- Amino-7-(2-di-4-oxo-phenyl)-4.methyl-6-(2-methyl-2-bromoline-4-yl-propyl)-7,8-dihydro-6H -11 than bite [4,3-d], ^_5_g^ 2-amino-7-(3'-dimethylamino-5-a-biphenyl-2-yl), 'methyl_7 , 8_ dihydro-6Η-» than bite [4,3-ci] pyridine-5-one; 2_amino group _:·[2·(2 wood dimethoxy _ money _5 base) 4. Fluoro-phenyl]_4 methyl-7,8-dihydro-6Η-pyrido[4,3-d]pyrimidin-5-one; 2_amino group_7_[4_fluoro_2_(5_ Methoxy n3_yl), stupidylmethyl-7,8-dihydro-6H-tonido[4,3-d]pyrimidin-5-one; 2-amino-7-(4-fluoropterin _5 Prepare phenyl)·4_methylmercapto-winter 4-leaf propyl)_7,8_dihydro_6Η-° than bite [4,3-d] squirting; 2-amino-7- [4ϋ(2·methoxyl-bite-3_yl)_stupyl]*_methyl winter (2-methyl: 2-Morline-4 winter propyl), 8_ dinitrogen collar, he Bite-5-嗣, 2-amino-o-fluoro_3,_methoxy, phenyl-2-yl)_4 2-morpholin-4-yl-propan, 〇* 1 Τ ^土)_7, 8_二虱-6Η-pyrido[4,3-d]pyrimidin-5-one; (R)-2-aminofluoro__(_methoxy-5-mercaptopurine __2_彳策基]_4-曱基-7 8-- & 疋2 base) Ben, ~虱-6Η-° than bite [4,3-d]. Midine-5-one; 2-amino-7-(4-Gu 1 + + , «比四Γ43(1) phenyl)-4-methyl-7,8-dihydro-6H_ 疋[4,3 -d], pyridine, 5 ketone and its stereoisomers <1*^, tautomers and pharmaceutically acceptable salts or prodrugs 0 144363.doc •52· 201032806 The above Hsp90 inhibitors (I) Examples of the compounds and methods of making the same are disclosed in U.S. Patent Application Publication No. 2007-0123546 A1, the entire disclosure of which is incorporated herein by reference. Other suitable Hsp90 inhibitors include the isoxazole derivatives of formula (D) and their domain isomers as well as salts, solvates and hydrates thereof, and prodrugs thereof

(D) wherein each R independently represents an optional substituent and r3 represents a carboxyguanamine group. Preferably, the present invention relates to compounds consisting of the formula (E) and

The use of its regioisomers and their salts, solvates and hydrates, and their prodrugs:

(E) wherein R3 represents an apodamine group (for example, ethylaminocarbonylCH3CH2NHC(=0)- or isopropylaminocarbonyl(CH3)2CHNHC(=〇)_); R·9 represents -CH2NR10Rn or _Nrior", wherein the substituted amine group NRR is a solubilizing group (e.g., fluorenyl, hexahydroacridinyl, piperazine 144363.doc-53-201032806, p-pyridyl, ethyl Amino, isopropylamino, diethylamino, cyclohexylamino, cyclopentylamino, methoxyethylamino, hexahydro-D-pyridyl-4, yl-N-ethinylpiperazine , N-methylpiperazinyl, methylsulfonylamino, thiomorpholinyl, thiomorpholinyl-dioxide, 4-hydroxyethylhexahydropyridyl, and 4-hydroxyhexahydro- And the Rs represents an optional substituent, especially a less lipophilic group (for example, ethyl, isopropyl, bromo or a gas). In the present invention, such a 5-substituted 2,4-di In a hydroxyphenyl compound, the hydroxyl group can be protected by a group which dissociates in the body to release a hydroxyl group. Such known prodrug-type groups which can be dissociated to produce a hydroxyl group include an alkylcarbonyloxy group (for example, a mercapto group) Oxy) and alkylaminooxy (e.g., dialkylamino- or isopropylamino-monooxy). Specific compounds to which the present invention relates include, in particular, the following salts, N-oxides, hydrates and solvates, and Drug: 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morphin-4-ylmethyl-phenyl)-iso- oxa Ethylamine 5-(2,4-mono-based-5-isopropyl-phenyl)_4-(4-hexahydro) butyl-1-ylmethyl-phenyl)-isoxazole-3-carboxylic acid Acetamide 4-(4-diethylaminomercapto-phenyl)-5-(2,4-dihydroxy-5-isopropyl-phenyl)-isoxazole-3-decanoic acid acetamidine 5 - (2,4-mono-based 5-5-isopropyl-phenyl)_4_[4-(4-indolyl-β-decylmethyl)-phenyl]-isoxazole-3-formic acid acetamide 5-(2,4-dihydroxy-5-isopropyl-phenyl)_4_(4-ethylaminoindenyl-phenyl)-isoxazole-3-carboxylic acid acetamide 5 (2,4 once 5-[4-isopropyl-benzyl]-4-[4-(isopropylamino-methyl)_144363.doc -54- 201032806 Phenyl]-isoxazole-3-decanoate 4-(4-Cyclohexylaminomethylphenyl)-5-(2,4-dihydroxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethylamine 4- [4 -(Tertiary butylamino-fluorenyl -phenyl]-5-(2,4-dihydroxy-5-isopropyl-phenyl-phenyl)-isoxazole-3-carboxylic acid acetaminophen • 5-(2,4-dihydroxy-5-iso Propyl-phenyl)-4-{4-[(2-decyloxy-ethylamino)-methyl]-phenylisoxazole-3-decanoate 5-(2,4 -dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenylφ)-isoxazole-3-carboxylic acid isopropyl decylamine 5-(2, 4-Dihydroxy-5-isopropyl-phenyl)-4-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-isoxazole_3·isopropyl isopropylate 5-decylamine 5-(5-tert-butyl-2,4-dihydroxy-phenyl)-4-[4-(4-methyl-piperazin-1-ylindenyl)-phenyl]-iso Oxazole-3·acetate formate 5-(5-t-butyl-2,4-dihydroxy-phenyl)-4-(4-hexahydropyridin-1-ylmethyl-phenyl)-iso Oxazole-3-carboxyacetamide 5-(2,4-dihydroxy-5-isobutyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenylphenanyl)-iso. Ethylene acetamide formate 5-(2,4-dihydroxy-5-isobutyl-phenyl)-4-(4-hexahydropyridin-1-ylindenyl-phenylisoxazol-3- Ethyl formate 5-(5-tert-butyl-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid Acetamide 5-(5-tert-butyl-2,4-dihydroxy-phenyl)-4-(4-diethylaminomethyl-phenyl)-isoxazole_3·formic acid acetamidine Amine 3-(5-chloro-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-iso 144363.doc •55· 201032806 Oxazole-5- Ethyl formate 4-(4-diethylaminomercapto-phenyl)-5-(4,6-di-based-2'-indolyl-biphenyl-3-yl)-isoxazole 4-(4-diethylaminomercapto-phenyl)-5-(4'-gas-4,6-di-trans-phenyl-3-yl)- Isoxazole-3-decanoate 4-(4-diethylaminomethyl-phenyl)-5-(4,6-dilight-biphenyl-3-yl)-isoxan Oxazol-3-formic acid acetamide 5-(2'-gas-4,6-di-trans-phenyl-3-yl)-4-(4- 0 piroxime-1 -ylmethyl-benzene -isoxazole-3-carboxylic acid acetamide 5-(4,6-dihydroxy-biphenyl-3-yl)-4-(4-morpholin-4-ylindenyl-phenyl)- Isoxazole-3-furoate B Indoleamine 5-(2,4-diyl-5-phenethyl-phenyl)-4-(4-oxaz-4-ylmercapto-phenyl)-isoxazole-3-decanoic acid Acetamide 5-(5-gas-2,4-diheptyl-phenyl)-4-(4-hexa-1βpyridine-1 -ylmercapto-phenyl)-isoxazole-3 - Isopropylamine decanoate 4-(4-diethylaminomethyl-phenyl)-5-(5-ethyl-2,4-di-phenyl-phenyl)-isoxazole-3 - acetamidine formate 5-(5-ethyl-2,4-diheptyl-phenyl)-4-[4-(4-methyl-branches-methyl-1 -ylindolyl)-phenyl] -isoxazole-3-formic acid acetamide 5-(5-ethyl-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-iso ° ° sit-3 - acetoacetate 5-(5-gas-2,4-dihydroxy-phenyl)-4-(4-diethylaminomethyl-phenyl)-isoxazole- 3-(5-gas-2,4-dizhao-phenyl)-4-[4-(4-indolyl-ninnyl-methyl-1-ylindenyl)- 144363. Doc -56- 201032806 Phenyl]-isoxazole-3-decanoate 5-(5-gas-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-yl) A compound of the formula (D) or the formula (E) and a process for producing the same are disclosed in WO 04/072051, published on Aug. 26, 2004. The case is hereby • incorporated by reference in the present application. A preferred compound is 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid Acetamide. ® Suitable mTOR inhibitors include, for example: I. Rapamycin' is derived from Streptomyces hygroscopicus (the immunosuppressant produced by Sirepiomycei), the indoleamine macrolide II. Rapamycin derivatives, for example: a· Substituted rapamycin 'e.g., 4 〇 〇 经 substituted rapamycin 'e.g. as in US 5,258,389, WO 94/09010, WO 92/

05179, US 5,1 18,677, US 5,1 18,678, US 5,100,883, US φ 5 > 151 > 413 ' US 5,120,842 'WO 93/1 1130 'WO 94/02136 'WO 94/02485 and WO 95/14023 All of these cases are incorporated herein by reference; b. 16-0-substituted rapamycin, for example, at w〇94/〇2136, .W〇95/16691 and WO 96/ The contents of such cases are incorporated herein by reference in their entirety by reference to the entire disclosure of the disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the entire disclosure of Us 5,256,79〇. 144363.doc •57· 201032806 d. Preferred rapamycin derivative system

Ri is CH3 or C3_6 alkynyl, R2 is hydrazine or -CH2-CH2-〇H, 3-hydroxy-2-(radiomethyl)_2-methyl-propenyl or tetrazolyl and X is =0, (H, H) or (H, OH) is restricted when X is = 〇 and R is CHS, r2 is not Η, or its prodrug 'when R2 is -CHrCH^OH, for example, physiologically Hydrolyzable ether. Compounds of formula 1 ' are disclosed, for example, in WO 94/09010, WO 95/16691 or WO 96/41807, each of which is incorporated herein by reference. Such compounds can be prepared in a manner similar to that disclosed or similar to those described in the references herein. Preferred mTOR inhibitor compounds are 32. deoxyrapamycin, 16_pent-2-ynyloxy-32-deoxyrapamycin, 16-pent-2-ynyloxy-32(S)-di Hydrogen-rapamycin, 16-pental-2-alkynyloxy-32(S)-dihydro-40-0-(2-hydroxyethyl)-rapamycin and more preferably, 40_ Indole (2-hydroxyethyl) rapamycin 'is disclosed in Example 8 of WO 94/09010. 144363.doc -58- 201032806 The rapamycin derivative of the genus 40 40 is 40-0-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy-2-(hydroxymethyl) -2-mercaptopropionate] rapamycin (also known as CCI779), 40-epi-(tetrazolyl)-rapamycin (also known as ABT578), 32-deoxyrapamycin, 16-pent-2-ynyloxy-32(S)-di-hydrorapamycin, or TAFA-93. e. The rapamycin derivative also includes the so-called rapalog analogs, for example, as disclosed in WO 98/02441 and WO 01/14387, for example, AP23573, AP23464 or AP23841. φ is based on the observed activity (for example, in combination with megalin protein-12 (also known as FK-506 binding protein or FKBP-12), for example, as in WO 94/09010, WO 95/16691 or WO 96/41 8 As described in 07), rapamycin and its derivatives have been found to be useful, for example, as immunosuppressants in the treatment of acute allograft rejection, for example. The present invention provides a pharmaceutical composition comprising: a) a compound of formula (E)

Wherein R3 is selected from the group consisting of ethylaminocarbonylCH3CH2NHC(=0)- or isopropylaminocarbonyl(ch3)2chnhc(=o)-), and R8 is selected from ethyl, isopropyl, bromo or chloro; And 144363.doc -59· 201032806 r9 is selected from the group consisting of linalyl, hexahydropyranyl, base, thiophene, ethylamino, isopropylamino, diethylamino, Cyclohexylamino, cyclopentylamino, methoxyethylamino, hexahydro.咬-4-yl, Ν-ethyl aryl base, fluorenyl-hydrazinopiperazinyl, fluorenylsulfonylamino, thiomorpholinyl, thiomorpholinyl-dioxide, 4- Alkyl hexahydroindenyl or 4-aminohexahydroindenyl; and b) at least one mTOR inhibitor. The compound of formula (E) may be an Hsp90 inhibitor. The compound of formula (E) may be 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylindenyl-phenyl)-isoxazole_3 _Acetylamine citrate. In another aspect, the invention provides a compound of formula or 5-(2 4 -dihydroxy-5-isopropyl-phenyl).4-(4-morpholin-4-ylindenyl-phenyl)-iso Use of oxazole-3-formate acetamide and at least one mTOR inhibitor for the manufacture of a medicament for the treatment or prevention of a proliferative disorder. In still another aspect, the present invention provides a compound of the formula or 5-(2,4-dihydroxy-5-isopropylphenylmorpholine-4-ylmethyl-phenyl)isoxazole_3_carboxylic acid Indoleamine and at least one mT〇R inhibitor for the treatment or prevention of proliferative diseases. In another aspect, the present invention provides a method of administering a compound of the formula or 5-(2,4-dihydroxy-5-isopropyl-phenyl)4 (4-morpholin-4-ylmethyl, stupid A method of treating or preventing a proliferative disease by using isoformazole-3-formic acid acetamide and at least one 111 guanidine 11 inhibitor. The mTOR inhibitor used in accordance with the present invention may be selected from RAD rapamycin (sirolimus) and its derivatives/analogs, for example, everolimus or; 144363.doc 201032806 CCI-779, ABT578, SAR543, Ascomycin (ethyl analog of FK506), AP23573, AP23841, AZD08055 and OSI027 ° The preferred mTOR inhibitor of the present invention is sirolimus and/or everolimus.子. Ascomycin, which is an ethyl analog of FK506. In each of the above-cited citations of the respective patent applications, the subject matter related to the compounds is hereby incorporated by reference. Also encompassing the pharmaceutically acceptable salts, corresponding racemic isomers, diastereomeric isomers, enantiomers, tautomers thereof, and the corresponding crystals of the compounds disclosed above disclosed therein Variants (when present), for example, solvates, hydrates, and polymorphs. Compounds useful as active ingredients in the combinations of the invention can be prepared and administered as described in the cited documents, respectively. Combinations of two or more independent active ingredients as described above are also within the scope of the invention, i.e., a pharmaceutical combination within the scope of the invention may comprise three or more active ingredients. In various embodiments, the mTOR inhibitor used in accordance with the invention may be selected from the group consisting of RAD rapamycin (sirolimus) and derivatives/analogs thereof, for example, vivam or RAD001; CCI-779, ABT578 , SAR543, ascomycin (ethyl analog of FK506), AP23573 and AP23841. - The term "mTOR kinase-dependent disease" includes, but is not limited to, the following symptoms: • Organ or tissue transplant rejection, for example, for treatment with, for example, heart, lung, combined heart-lung, liver, kidney, pancreas A recipient of a dirty, skin or corneal transplant; graft versus host disease, for example, the following bone marrow transplant; 144363.doc -61 - 201032806 • Restenosis syndrome, such as tuberous sclerosis or Cowden's disease (c 〇wden Disease) #Retinitis pigmentosis Autoimmune diseases include encephalomyelitis, human sputum-dependent diabetes, lupus, dermatomyositis, arthritis and rheumatic diseases Steroid-resistant acute lymphoblastic leukemia • Fibrotic diseases including scleroderma, pulmonary fibrosis, renal fibrosis, cystic fibrosis • Pulmonary hypertension • Immunomodulation • Multiple sclerosis • VHL syndrome • Cana synthesis Carney complex • Familial colorectal polyps • Juvenile polyposis syndrome • Bir.t_Hogg-Duke syndrome • Familial hypertrophy Myopathy • Woolf-Parkinson-White ('^〇1£-?&41118〇11-?'1146) Syndrome • Neurodegenerative disorders, for example, Parkinson's caused by tau mutation, Huntingtin's, Alzheimer's and dementia, type 3 spinal auditory cerebellar ataxia, motor neuron disease caused by SOD1 mutation, waxy lipid storage disease / 144363 .doc •62· 201032806

Batten disease (children's neurodegeneration) • Wet and dry macular degeneration

• Muscular atrophy (atrophy, cachexia) and myopathy, for example, Dann's disease • Bacterial and viral infections, including M tuberculosis, Group A streptococci, Type I HSV , HIV infection • Neurofibromatosis, including neurofibromatosis type 1 , • Peutz-Jeghers syndrome

Furthermore, "mTOR kinase-dependent diseases" include cancer and other related malignancies. A non-limiting list of cancers associated with the pathological mT0R signaling cascade includes breast cancer, renal cell carcinoma, gastric tumors, neuroendocrine tumors, lymphoma, and prostate cancer. Examples of proliferative diseases that can be treated with a combination of an HSP90 inhibitor and a combination of a dicing agent or a pharmaceutical agent of the invention are, for example, a conscience or malignancy, a brain cancer, a kidney cancer, a liver cancer, an adrenal cancer. , bladder cancer, breast cancer, abdominal cancer, gastric cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal or thyroid carcinoma, genitourinary area Carcinoma, melanoma, glial fistula, sarcoma, glioblastoma, multiple myeloma or gastrointestinal cancer, especially colon cancer or colorectal cancer or neck and head tumor, epidermal hyperplasia, dryness, prostate Hyperplasia, neoplasia, u I ι4_ epithelial features of neoplasia, neuroblastoma, lymphoma, breast cancer, or leukemia. In particular, the compositions of the invention are particularly suitable for breast tumors; epidermoid tumors, for example, For treatment: epidermoid head and / or neck

144363.doc -63- 201032806 Tumor or oral tumor; lung tumor 'for example, small cell or non-small cell lung tumor; gastrointestinal tumor, for example, colorectal tumor; or genitourinary tumor, for example, prostate tumor (especially hormone Prostate tumors that are difficult to treat; or (11) proliferative diseases that are difficult to treat with other chemotherapeutic agents, or (in) tumors that are difficult to treat with other chemotherapeutic agents due to multiple drug resistance. In a broader sense of the invention, the proliferative disease may be a hyperproliferative condition such as leukemia such as 'acute myeloid leukemia, eg 'chronic myeloid leukemia, eg 'chronic lymphocytic leukemia, eg eg Acute lymphoblastic leukemia, such as 'multiple bone tumors, eg, lymphoma, and/or can be used to treat myelodysplastic syndromes, systemic mastocytosis, hyperproliferation, fibrosis (especially pulmonary fibrosis, but Other types of fibrosis, for example, renal fibrosis), angiogenesis, dryness, atherosclerosis, smooth muscle hyperplasia in blood vessels such as stenosis or restenosis after angioplasty, VQn Hippel Lindau syndrome, multicenter Castleman disease and / or psoriasis. Combinations of the invention may also be used to prevent or treat diseases caused by permanent angiogenesis, such as cognac; Kaposi's sarcoma (Kap〇si, s s(10)" restenosis, such as 'stent-induced restenosis; Endometriosis; Crohn's disease; Hodgkin's disease (H〇dgkin, s-called; platinum disease; arthritis 'for example, rheumatoid arthritis; hemangioma; angiofibroma; Eye diseases such as diabetic retinopathy and neovascular glaucoma; kidney diseases such as glomerulonephritis; diabetic god 144363.doc -64 - 201032806 transsphenoidal; malignant nephrosclerosis; thrombotic microvascular disorder; transplant rejection and kidney Small ball disease; fibrotic diseases, for example, liver cirrhosis; mesangial cell proliferative diseases; arteriosclerosis; nerve tissue damage; and as an immunosuppressive agent, as a non-marking wound healing aid for use after balloon catheter treatment, For use in artificial blood vessels or to inhibit revascularization after insertion into a mechanical device that maintains blood vessels (eg, 'stents'); and for the treatment of age spots and contact The combination of the invention includes the use for the treatment, prevention or inhibition of diseases characterized by cell proliferation and inflammatory cell infiltration, such as inflammation, rha, asthma, chronic bronchitis, atherosclerosis and transplant rejection. In the case of a tumor, tumor disease, cancer or cancer, the other option is or otherwise covers the initial organ or tissue and/or any other location: metastasis, regardless of the location of the tumor and/or metastasis. In an embodiment, the invention provides the use of a combination of a first pharmaceutical component disc mT〇R inhibitor of the invention for the manufacture of a medicament for the treatment or (d) proliferative disease. In yet another embodiment, the invention provides A combination of a first pharmaceutical component of the present invention and an mTOR inhibitor for use in the treatment or prevention of a proliferative disorder. Suitable clinical studies may be, for example, public exposure, dose escalation studies for patients with proliferative diseases. In other words, these studies demonstrate synergistic effects of the various active ingredients of the combinations of the present invention, which can be studied by those skilled in the art who are familiar with the art. The results directly determine the beneficial effects on proliferative diseases. Specifically, 'Study 9 can be applied to compare the effects of a combination of a single therapy using an active ingredient with the present." Preferably, the drug 144363. Doc >65- 201032806 The dose of agent (a) is administered until the maximum tolerated dose is reached and the agent is administered in a fixed dose. Alternatively, the agent (a) can be administered in a fixed dose and the agent (b) The dose is increased. Each patient may receive several doses of the agent (a) per week or intermittently. The efficacy of the treatment may be determined in these studies, for example, by performing a symptom score every 6 weeks at 12 weeks, 18 Measured weekly or after 24 weeks. The administration of the pharmaceutical combination of the present invention not only achieves a beneficial effect (e.g., a synergistic therapeutic effect, e.g., in slowing, as compared to a monotherapy using only one pharmaceutically active ingredient used in the combination of the invention) Delaying the progression of symptoms or inhibiting symptoms) and can also achieve surprisingly additional benefits (eg, reducing side effects, improving quality of life or reducing morbidity. Additional benefits may be The dosage of the active composition of the present invention to the parts' example 'of such dosage requirements not only often be smaller but are also applied less frequently' This can reduce the incidence or severity of side effects. This is consistent with the expectations and requirements of the patient being treated. It is an object of the present invention to provide a pharmaceutical combination, such as a composition comprising - quantifying a first component and a second component as previously described, which may be effective for combination therapy in the case of a silky or proliferative disease. These first and second sets of injuries can be provided for administration in a fixed '' and sigma (ie, in a single galenic formulation composition) which may be known per se for use in the gut (eg, orally or rectally) And non-intestinal administration, including mammals (warm-blooded animals), including humans, in combination with one or more of the four carriers or carriers, which are especially suitable for enteral or parenteral administration. . Another option is that the combination can be + g _ doctor

The first component is provided as a separate set of 'medical doses that are included in the kit t or not sold as a kit for 144363.doc * 66 - 201032806. Pharmaceutical compositions which are administered separately from the first component and the second component can be prepared in a manner known per se and are suitable for use in the gut (eg, orally or rectally) and parenterally, including humans. Mammal (warm-blooded animal). Each such composition for independent administration comprises a therapeutically effective amount of at least one pharmacologically active component in association with one or more pharmaceutically acceptable carriers or diluents.

The term "pharmaceutical component" and the term "pharmaceutical agent" or "active ingredient" are used. The suitable medical composition may contain, for example, from about 0.1% to about 99.9%, preferably from about 1% to about 6%. Active ingredient. For example, pharmaceutical preparations for combination treatment by enteral or parenteral administration are in unit dosage form, such as sugar-coated lozenges, remedies, capsules or suppositories or ampoules. Unless otherwise stated, the :: type is prepared in a manner known per se, for example by means of conventional mixing. , granules, sugar coating, dissolution or; East dry method. It should be understood that the dosage units of the pharmaceutical compositions contained in the other dosage forms do not themselves constitute an effective amount. The effective amount required can be achieved by administering a plurality of dosage units to a group. In the method of sexually transmitted diseases, the first component and the first component can be administered in a sequential, sequential or separate manner. The first and second components can be delivered in unit dosage form or in multiple separate unit dosage forms. In general, a therapeutically effective amount of each of the pharmaceutical compositions of the present invention can be administered simultaneously and in any order, and such components can be used alone or in a fixed set. For example, the method for preventing or treating a proliferative disease of the present invention, I44363.doc-67-201032806 2, may comprise (d), or in a therapeutically effective amount, preferably in a synergistically effective amount (for example, The daily or intermittent dose corresponds to the first component of the above-mentioned (1) administration of the free or pharmaceutically acceptable salt form and (9) the administration of the second group in the form of a free or pharmaceutically acceptable hydrazine. 2. The component of the combination of the present invention may be administered separately in different two periods during the treatment time course or in separate or separate combinations. Further, the term "investment" also covers the use of a combination group. For the prodrug, the combination of the former (4) and the (4) composition, the present invention should be understood to refer to all of the simultaneous or alternating treatments and the term "administration" should be understood accordingly. The effective dose of the component may depend on the compound or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition being treated. Therefore, the dose of the combination of the present invention should be based on a variety of factors ( Including investment Route and patient's kidney and liver sputum) (4) Choose a clinician or physician with general skills to reduce or reduce the effectiveness of the individual active ingredients required to prevent or progress the condition and prescribe the prescription. The optimal accuracy of the concentration of active ingredient in a range that produces efficacy and is non-toxic requires a dosage regimen based on the kinetics of active filament site utilization.

Η α, — The amount of the active ingredient of the dosage form should be treated: the treatment: the main and specific mode of administration changes. However, it should be understood that the specific dose of the patient should be determined by a variety of factors including the activity of the specific compound used, the age, weight, overall health, sex, gestation, and administration of the patient. Time, route of administration, rate of excretion 144363.doc -68- 201032806 degrees, drug combination and severity of the particular disease being treated. For a given situation, a therapeutically effective amount can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician. For the purposes of the present invention, a therapeutically effective amount can generally mean a total sputum dose administered to a subject in a single or multiple doses, which may be, for example, from 0.001 to 1000 mg/kg body weight per twentieth and more preferably Daily 〇 to 3 〇 / "weight. Therefore, the unit dose composition may contain a combination of these amounts or multiple thereof to form a daily dose. Compounds of formula (I), mTOR inhibitors and inclusions The pharmaceutical composition of the active ingredient can be administered orally, parenterally, sublingually, by nebulization or inhalation spray, rectally, or externally to contain the desired non-toxic pharmaceutically acceptable carrier, adjuvant. And the dosage unit formulation of the vehicle is administered. The topical administration may also involve transdermal administration, for example, the use of a transdermal patch or an ion electrophoresis device. The term "parenteral" as used herein includes subcutaneous injection, intravenous injection, muscle. Internal injection, intrasternal injection, or infusion technique. Injectable preparations, e.g., money injectable aqueous suspensions or oil suspensions, may be employed in accordance with known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, e.g., a solution in sputum, 3-propanediol. Among the acceptable vehicles and solvents may be water, Ringer's solution, and isotonic sodium chloride solution. In addition, it is common to use a non-fixed oil as a solvent or a suspending medium for any of the following: any of: a dish and a fixed oil 'including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. 144363.doc -69- 201032806 A suppository for rectal administration can be prepared by combining the drug with a suitable non-irritating form such as cocoa butter and polyethylene glycol. The non-irritating excipient is at room temperature. It is a solid but liquid at the rectal temperature and therefore it will melt in the rectum and release the drug. Solid dosage forms for oral administration may include capsules, troches, pills, powders, and granules. In such solid forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. As a matter of practice, the dosage forms may also contain additional materials other than inert diluents, such as 'smoothing agents' such as stearyl. In the case of capsules, binders and pills, the dosage forms may also contain buffering agents. Tablets and pills may additionally be prepared by enteric coating. Liquid dosage forms suitable for oral administration may include (iv) acceptable emulsions, solutions, suspensions, syrups and elixirs containing such inert diluents as are commonly employed in the art, such as water, and may also include Agents such as wetting agents, emulsifying agents and suspensions (tetra), cyclodextrin, and sweet (iv), materials and flavoring agents. The compound of the formula (1), the mTOR_agent and the pharmaceutical composition described above are also in the form of sigma and ruthenium. As is known in the art, the plastids are usually derived from scales or other lipids. Liposomes can be formed by mono- or smectic hydrated liquid crystals dispersed in an aqueous medium. Any physiologically acceptable and metabolizable non-toxic lipid f which forms a lipid body can be used. The composition of the present invention in the form of a liposome, in addition to the compound of the present invention, may also contain a stabilizer antiseptic excipient and the like. Preferred lipids are natural and synthetic phospholipids and phospholipid choline (lecithin). A method of forming a liposome is known from the art 144363.doc 201032806. See, for example, prescott (editor), "Meth〇d in Cell

Biology," (Vol. XIV, Academic Press, New York, 1976, p. 33 et seq., etc.). In addition to being combined with an mTOR inhibitor, the Hsp9(R) compound of the present invention may also be combined with one or more other pharmaceutical agents. These agents can be ACE inhibited • Qi! ; adenosine kinase inhibitor; zozi 1; adrenal cortical antagonist; AKT pathway inhibitor; stimulator; angiogenesis inhibitor; angiogenesis-inhibiting steroid; anti-androgen; anti-estrogen; anti-high blood cut Anti-leukemia chelate, antimetabolite; anti-proliferative antibody; cell>inducer of apoptosis; AT1 receptor antagonist; aurora kinase inhibitor; aromatase inhibitor; bioreactive enamel, bisphosphonate, Bruton's (Brut〇n, s) glutamate kinase (BTK) inhibitor, calcineurin inhibitor; CaM kinase worker ice formulation; tyrosine nitrite inhibitor; CDC25 phosphatase inhibitor; chk kinase Inhibitor; a compound that positively/lowers protein or lipid kinase activity or protein or lipid phytase activity' another anti-angiogenic compound or a compound that induces a cell cleavage process; used to regulate genistein, Oromo Modulator of olomoucine and/or tyrosine phosphorylation inhibitor; cyclooxygenase inhibitor, RAF kinase inhibitor; cyclin-dependent kinase inhibitor; cysteine protease inhibitor; Injecting agent; cleavage agent; operative enzyme inhibitor; coffee binder; endocrine hormone; ruthenium thiotransferase inhibitor; (iv) kinase inhibitor; support, reduction or inhibition of live [biochemical, gonar Lin (g〇nad〇reiin) agonist; glycogen synthase kinase-3 (GSK3) inhibitor; heparanase inhibitor; agent for the treatment of hematological malignancies; histone deacetylase (10) AC) inhibition 144363.doc •71 - 201032806 Implants containing corticosteroids; I-κ Β-α kinase inhibitor (IKK); insulin receptor tyrosine kinase inhibitor; c-Jun N-terminal kinase (JNK) Kinase inhibitor; microtubule adhesive; mitogen-activated protein (MAP) kinase-inhibitor; MDM2 inhibitor; MEK inhibitor; methionine aminopeptidase inhibitor; matrix metalloproteinase (MMP) inhibitor; Monoclonal antibody; NGFR tyrosine-kinase-inhibitor; p3 8 MAP kinase inhibitor, including SAPK2/p38 kinase inhibitor; p56 tyrosine kinase inhibitor; PDGFR tyrosine kinase inhibitor; phospholipid creatinine 3 - kinase inhibitor; phosphatase inhibitor; photodynamic therapy; platinum agent; White phosphatase inhibitors, including PP1 and PP2 inhibitors and tyrosine phosphatase inhibitors; PKC inhibitors and PKC δ kinase inhibitors; polyamine synthesis inhibitors; proteosome inhibitors; ΡΤΡ1Β inhibitors; protein tyrosine Kinase inhibitors, including SRC family amino acid kinase inhibitors; Syk tyrosine kinase inhibitors; and JAK-2 and/or JAK-3 tyrosine kinase inhibitors; Ras oncogenic subtype inhibitors; retinoids; ribose Nucleotide reductase inhibitor; RNA polymerase II elongation inhibitor; S-adenosylmethionine decarboxylase inhibitor; serine/threonine kinase inhibitor; somatostatin receptor antagonist; sterol Biosynthesis inhibitors; telomerase inhibitors; topoisomerase inhibitors; means of destruction of tumor cells; monoclonal antibodies to VEGF or VEGFR; VEGFR tyrosine kinase inhibitors; or RANKL inhibitors. Specific examples of compounds which can be combined with the Hsp90 inhibitors of the invention are CIBACEN; benazepril; enazepril; captopril; enalapril; Finsinopril; lisinopril; moxipril 144363.doc -72- 201032806 (moexipril); quinapril; ramipril; Perindopril; trandolapril; 5-deuterostatin; Leucovorin; Levamisole; Mitotane; (Deguelin); Trciribine; Chlorambucil; Cyclophosphonium; Adacarb; Dacarbazine; Lomust; Lomustine; Procarbazone Procarbazine) ; ° Thiotepa; Melphalan; Temozolomide; Carmustine; Heterocyclic Amidine; Mitomycin; Hexamidine (Altretamine); Busulfan; Machlorethamine hydrochloride; sulfhydrylamine; streptozotocin Reptozocin); estramustine; Fumagillin; Shikonin; Tranilast; ursolic acid; suramin; Thalidomide; anecortave; triamcinolone; hydrocortisone; ll-α-epitope® hydrocortisol; 11-dehydrositosterol (cortexolone); 17α-methionine; corticosterone; deoxycorticosterone; testosterone; estrone; dexamethasone; nilutamide; bicalutamide; toremifene ;Letrozole; Testolactone; Anastrozole; Bicalutamide; Flutamide; Tamoxifen Citrate; Exemestane (Exemestane); fulvestrant; tamoxifen; I vesistry 144363.doc -73- 201032806 (fulvestrant); raloxifene; raloxifene hydrochloride ; Shixiao acid recorded (III) hydrate; pamidronate disodium; Ara-C; hypoxanthine 6-基基嗓"令(6-MP); fludarabine phosphate; cytarabine; Fludarabine; Flexuridine; fluoropurine bite (Fluorouracil); Capecitabine; raltitrexed; methotrexate; Cladribine; gemcitabine; gemcitabine hydrochloride; thioguanine Thioguanine); transurea; 5-azacytidine; decitabine; edatrexate; pemetrexed; bevacizumab; rituximab Antibiotic (rituximab); PR064553; ethanol, 2-[[3-(2,3-diphenoxy)propyl]amino]-(9C1); gambogic acid; Embelin Arsenic trioxide; DIOVAN; Binucleine 2; atamestane; exemestane; formestane; aminoglutethimide; roglethimide; Pyridoglutethimide; trilostane; testosterone vinegar; ketoconazole; vorozole; fadrozole; ana曲β坐;来曲《坐; lymphokine; interferon γ; etidonic acid (etridonic); clodronic acid; tiludronic; pamidronic acid (pamidronie); Alendronic; ibandronic; risedronic; ° zoledronic acid; terreic acid; cysteine vinegar (Cypermethrin); 144363.doc -74- 201032806 >Deltamethrin, Fenvalerate; cool amine linonic acid inhibitor 8; 5-isoquinoline sulfonic acid, 4-[(2S)-2 -[(5-isoquinolinyl fluorenyl)methylamino]-3-oxo-3-(4-phenyl-i-piperazinyl)propyl]phenyl ester (9CI); benzene Sulfonamide, N-[2-[[[3-(4-phenylphenyl)-2-propenyl]methyl])]amino]indolyl]phenyl]-indole-(2-hydroxyethyl) 4-methoxy-(9C1); phosphonic acid, . [[2-(4-bromophenoxy)-5-nitrophenyl]hydroxymethyl]-(9C1); M-naphthalenedione, 2,3-bis[(2-hydroxyethyl)thio]-(9C1); Debromohymenial disine; 7H-° piroxime [2,3-d]° seductive derivative, φ Including {6-[4-(4-ethyl-piperazin-1-ylmethyl)-benzene -7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-l-phenyl-ethyl)-amine; BAY 43-9006; (4-tert-butyl _ Phenyl)-94-»biti-4-ylmethyl-isoindolin-1-yl)-amine; imatinib; SU101; SU6668; GFB-111; 4-amino-5-benzene -7-cyclobutyl-pyrrolo[2,3-d]pyrimidine derivative (AEW541); PD180970; AG957; NSC 680410; PD173955; BMS354825; midostaurin; UCN-01; (safingol); BAY 43-9006; Bryostatin 1; Perifosine; _ Ilmofosine; RO 318220; RO 320432; GO 6976; Isis 3521 ; LY33353 1/LY379196 PD184352 ; . QAN697 ; Imatinib mesylate (GLEEVEC); tyrosine phosphorylation

Inhibitor or pyrimidinyl benzyl carbamide and its derivatives; tyrosine phosphorylation inhibitor A23/RG-50810; AG 99; tyrosine phosphorylation inhibitor AG 213; tyrosine phosphorylation inhibitor AG 1748; tyrosine phosphorylation inhibitor AG 490; tyrosine phosphorylation inhibitor B44; tyrosine phosphorylation inhibitor B44(+) enantiomer; tyrosine phosphorylation inhibitor AG 555 ; AG 144363 .doc -75- 201032806 494; tyrosine phosphorylation inhibitor ag 556 ; AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]aminobenzoic acid Burning vinegar 'NSC 680410, adafutin;); phosphatase i; phosphatase 2A; PTEN; 〇kadaic acid; TNP-470; retinoic acid, α-, γ- or δ_ Tocopherol or α_, γΓ4δ_tocotrienol; daidzein; iso-olomoxine; tyrosine phosphorylation inhibitor 丨; 1Η_Π 哚-3-acetamide, 1-(4- Gasbenzhydryl)_5_methoxy-2-indolyl-indole_(2_stylethyl)-(9Cl); 5-alkyl substituted 2-arylaminophenylacetic acid; Celecoxib; rofecoxib; etoricoxib; Valdecoxib; 5_ thiol_2_(2|_ chloro.6, _aerocarbyl) phenylacetic acid 'lumicoxib; 3-(3,5-dibromo-4- Hydroxybenzylidene)-5-iodo-1,3-dihydroindol-2-one; benzamidine, 3-(dimethylamino)-N-[3-[(4-hydroxyphenyl) Mercapto)amino-4-methylphenyl]-(9C1); N9-isopropyl-ornomostar; olomostar; Purvalanol B; cyclin-dependent kinase (Roscovitine ); Indirubin; Kenpaullone; Pulvano A; Indirubin-3'-monoterpene; 4-morpholinecarbamamine, N-[(lS)-3-fluoro-2 -Phenoxy-1-(2-phenylethyl)propyl]amino]-2-oxo-l-(phenylmethyl)ethyl]-(9C1); Plicamycin ); Dactinomycin; Bleomycin; N-((3,3,3-trifluoro-2-trifluoromethyl)propanyl)sulfonamide; FTY720; Leuprolide; megestrol acetate; tyrosine phosphorylation inhibitor 23; tyrosine phosphorylation inhibitor 25; tyrosine phosphorylation inhibitor 47; tyrosine phosphorylation inhibitor 51 Tyrosine phosphorylation inhibitor AG 825 ; 2-prop Indoleamine, 2-cyano 144363.doc -76- 201032806 yl-3-(3,4-dihydroxyphenyl)-:^-phenyl-, (2£)-(9(:1); tyrosine Phosphorylation inhibitor Ag 1478; Lavendustin A; 3-0 than acetonitrile, ct-[(3,5-dichlorophenyl)methylene]-, (aZ)-(9Cl); Tyrosine phosphorylation inhibitor 46 ; a-hydroxyfarnesylphosphonic acid; butyric acid, 2-[[(2S)-2-[[(2S,3S)- ' 2-[[(2R)-2- Amino-3-mercaptopropyl]amino]-3-methylpentyl]oxy]-1-yl.lacyl-3-phenylpropyl]amino]-4-(indenyl) )-'1-methylethyl vinegar' (2S)-(9cl); Manumycin A; 2-propenylamine, 2-cyano-3-[4-hydroxy-3,5-double ( 1-mercaptoethyl)phenyl]-N-(3-phenylpropyl)-, (2E)- # (9C1) ; N-benzimidyl- staurosporine (PKC412) Miltonidine; SU11248; MLN518; abarelix; goserelin; goserelin acetate; indirubin-3'-monoquinone; PI-88; - Arabidinos (also known as arabinofuranosylcytosine); Bisulfan; N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1Η-吲哚-3-yl)) Ethyl]-amino]mercapto]phenyl]-2E- 2-propenylamine and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-

2E-2-propenylamine and its pharmaceutically acceptable salt (LBH589); cycloheptin A decyl aniline hydroxamic acid; [4-(2-amino-phenylaminoglycolyl)-benzyl Pyridin-3-ylmethyl carbamate and its derivatives; butyric acid; pyroxamide; trichostatin A; oxavastatin (OxamHatin); Decicidin; Depsipeptide; depudecin; trapoxin; debudcine; HC toxin; sodium phenylbutyrate; cycloheptyl bis-hydroxamic acid; Trichostatin A; 17-allylamino- 17-demethoxygaldanamycin (17AAG); geldanamycin, 17-deoxyl-17-(2 -propenylamino)- 144363.doc -77- 201032806 (9C1); geldanamycin; fluocinolone; dexamethasone; 2-acrylonitrile, 3-[(4-methylphenyl) Sulfosyl]-, (2E)-(9C1); hydroxy-2-naphthylmethylphosphonic acid; pyrazolone; gallic acid epigallocatechin; sulphuric acid sulfate; vinca sulfate Test; Vindesine; Vinorelbine; Docetaxel; Paclitax Xel); vinorelbine; discoid mollusc; cochicine; epothilone derivative; epothilone B; Epothilone A; Indoleamine, N-[2-[[[3-(4-chlorophenyl)-2-propenyl]indolyl]amino]indolyl]phenyl]-N-(2-hydroxyethyl)- φ 4-methoxy-(9C1); trans-4-iodo, 4'-boranyl-chalcone; succinonitrile, bis[amino[2-aminophenyl)thio]arylene ]-(9C1); Bengamide or its derivatives; Actinonin; gallic acid, gallic acid, gallic acid; marimastat; Prinomastat; metastat; BMS-279251; BAY 12-9566; TAA211; MMI270B; AAJ996; bevacizumab; Ibritumomab tiuxetan; tositumomab Iodine I 131; tyrosine phosphorylation inhibitor AG 879 ; phenol, 4-[4-(4-fluoroindolyl)-5-(4-pyridyl)-1Η-imidazol-2-yl]- (9C1); benzoguanamine, 3-(dimethylamino)-N-[3-[(4-hydroxybenzylidyl)amino]-4-methylphenyl]·(9C1); Damnacanthal; lysine acid deacidification Inhibitor 46; tyrosine phosphorylation inhibitor AG 1296; tyrosine phosphorylation inhibitor 9; 1,3-butadiene-1,1,3-tricarbonitrile, 2-amino-4-(1Η-吲哚-5-yl)-(9Cl); wortmannin; quercetin dihydrate; cantharidic acid; cantharidin; L-leucine guanamine, 144363 .doc -78- 201032806 N-[4-(2-carboxyvinyl)phenylindenyl]glycidyl-L-α-glutamic acid-, (E)-(9C1) ; VISUDYNE ; Porfimer sodium; Carboplatin; Cisplatin; Oxaliplatin; cisplatinum; Satraplatin, such as ZD0473; plaque•acid; ;LP-bromotetrazide oxalate; 2(5H)-furanone, 4-hydroxy-yl-5-(hydroxymethyl)-3-(1-o-oxyhexadecyl)-, (5R )-(9C1); benzylphosphonic acid; 1-1-1-pyrrolo-2,5-dione, 3-[1-[3-(didecylamino)propyl]-1H-indole-3 -yl]-4-(1Η-indol-3-yl)-(9Cl); bis-indenyl-malay Φ quinone imine IX; sphingosine; staurosporine; tyrosine phosphate Inhibitor 51; Hypericin; crude chopped wood (Rottlerin); DMFO; alacinomycin A; gliotoxin; PS-341; MLN 341; bortezomib; Velcade; L- leucine Amine, N-[4-(2-carboxyvinyl)benzhydryl]glycine-L-α-glutamic acid-, (E)-(9C1); tyrosine phosphorylation inhibitor AG 126; tyrosine phosphorylation inhibitor Ag 1288; tyrosine phosphorylation inhibitor Ag 1295; geldanamycin; genistein; PP1; PP2;

AW 1,2-benzenediol, 4-[(1Ε)-2-(3,5-dihydroxyphenyl)vinyl]-(9CI); tyrosine phosphorylation inhibitor AG 490; 2-naphthyl Vinyl ketone; 1^-744832; DK8G557; R115777; Isotretinoin; Tretinoin; fludarabine; ara-C; 6-sulfur bird raft; 5-FU; Bis; 6-mercaptopurine; pentostatin; 5,6-di-gas-1-β-D-ribofuranosylbenzimidazole; 2-aminopurine; terbinadine ; telomestatin; topotecan; gimatecan; irinotecan 144363.doc -79· 201032806 (irinotecan); camptothecin; 9- sure Tree test; PNU-166148; 10-hydroxycamptothecin acetate; etoposide; idarubicin hydrochloride; irinotecan hydrochloride; teniposide; Topotecan hydrochloride; doxorubicin; epirubicin hydrochloride; mitoxantrone hydrochloride; daunorubicin hydrogen acid Salt; doxorubicin; epirubicin; idabidin; Nemorubicin; losoxantrone; tenipop; etoposide; mitoxantrone; 1-(4-anilino)-4-(4-«pyridinium Methyl)pyridazine or a pharmaceutically acceptable salt thereof; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; rhuMAb; RHUFab; pegaptanib sodium (Macugen); Angiozyme Avastan 3-(4-Dimethylaminobenzylidene)-2-indololinone; denosumab ° The term "ACE inhibitor" as used herein includes, but is not limited to, CIBACEN, benapu LOT, LOTENSIN, captopril, enalapril, fosinopril, lisinopril, moxipril, quinapril, ramipril, perindopril And group Dopply. The term "adenosine kinase inhibitor" as used herein relates to a compound which targets, decreases or inhibits the metabolism of nucleobases, nucleosides, nucleotides and nucleic acids. An example of an adenosine kinase inhibitor includes, but is not limited to, 5-iodo-killing tuberculin, which is also known as 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-iodo-7-β- D-ribofuranosyl-(9C1). The term "adjuvant" as used herein refers to a compound which enhances 5-FU-TS linkage 144363.doc-80-201032806 and which is capable of drying, reducing or inhibiting phytase. Examples of adjuvants include, but are not limited to, formazan tetrahydrofolate and levorotatory saliva. The term "adrenal cortical antagonist" as used herein relates to a compound which targets, reduces or inhibits the activity of the adrenal cortex and alters the peripheral progeny of corticosteroids resulting in a decrease in 17-hydroxycorticosteroids. An example of an adrenal cortex-antagonist includes, but is not limited to, mitoxantrone. The term "purine pathway inhibitor" as used herein relates to a compound which targets, decreases or inhibits cell proliferation. Akt, also known as protein kinase beta ❿ (PKB), a serine/threonine kinase, is a key enzyme involved in several signal transduction pathways in diabetes. The major role of Akt in cells helps growth factor-mediated cell survival and arrests apoptotic cell death. One target for AKT pathway inhibitors includes, but is not limited to, Pi3K/AKT. Examples of AKT pathway inhibitors include, but are not limited to, deguelin, which is also known as 3H_bis(1)benzopyrano[3,4-1?:6,5,-6]pyran-7 (7& 11)-ketone, 13,133-dihydro-9'1〇-dimethoxy-3,3-dimethyl-, (7aS,13aS)-(9Cl); and Tacrine 0, also It is called 1,4,5,6,8-pentazaindan-3-amine, 1,5-dihydro-5-mercapto-purine-β-D-ribofuranosyl-(9C1). The term "alkylating agent" as used herein relates to a compound which causes DNA alkylation and which results in DNA molecule cleavage and double-strand cross-linking, thereby interfering with dNA replication and RNA transcription. Examples of alkylating agents include, but are not limited to, chlorambucil, cyclophosphamide, dacarbazine, lomustine, procarbazine, thiotepa, melphalan, temozolomide (TEMODAR), carmust Tetamine, ifosfamide, mitomycin, hexamethamine, busulfan, dichloromethyldiethylamine hydrogenate, nitrosourea (BCNU or GHadel), streptozotocin, and estramustine 144363.doc -81 - 201032806 Division > Ding. Cyclosporin can be administered, for example, in the form as it is marketed (e.g., under the trademark CYCLOSTIN); and ifosfamide can be administered by HOLOXAN. The term "angiogenesis inhibitor" as used herein relates to a compound that targets, decreases or inhibits neovascularization. Targets for angiogenesis inhibitors include, but are not limited to, methionine aminopeptidase-2 (MetAP-2), macrophage inflammatory protein-1 (ΜΙΡ-1α), CCL5, TGF-β, lipoxygenation Enzymes, cyclooxygenases, and topoisomerases. Targeting sites for angiogenesis inhibitors include, but are not limited to, ρ21, p53, CDK2, and collagen synthesis. Examples of angiogenesis inhibitors include, but are not limited to, fumagillin, which is referred to as 2,4,6,8-tetradecenedioic acid, mono[(3R,4S,5S,6R)-5-methoxy·4 -[(2ΙΙ,3Κ_)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]oxaspiro[2 5]octyl-6-yl]ester, (2E, 4E,6E,8E)-(9CI); shikonin, also known as diketone, 5,8-dihydroxy-2-[(1R)-i-hydroxy- 4 fluorenyl _3·pentenyl ]_(9CI); Tranilast, also known as benzoic acid, 2_[[3_(3,4-dimethoxyphenyl)b-oxy-2-propenyl]amino]_(9 (::1); ursolic acid; suramin; and thalidomide. As used herein, "angiogenesis-inhibiting steroids" include, but are not limited to, agents that block stagnation or inhibit angiogenesis, such as, for example, Anai. But he, triamcinolone, hydrocortisone, U_a• epitope hydrocortisol, u_deazapiritol, 17a-pyprogesterone, cortex, deoxycorticuridine, pen 嗣, although 嗣 and * Dexamethasone. As used herein, the term "antiandrogen" is a compound that blocks the effects of androgens derived from the adrenal gland and the testis. These androgens stimulate normal and malignant Prostate tissue growth. Examples of anti-androgens include, but are not limited to, 144363.doc • 82 - 201032806 luminol; bicalutamide (CASODEX), which can be formulated as disclosed in, for example, U.S. Patent No. 4,636,505. .

The term "antiestrogens" as used herein relates to compounds which antagonize the action of estrogen on the estrogen receptor layer. Examples of antiestrogens include, but are not limited to, toremifene; letrozole; testosterone; anastrozole; bicalutamide; flutamide, tamoxifen citrate; exemestane; Division; tamoxifen; fulvestrant; raloxifene and raloxifene hydrogenate. Tamoxifen can be administered in the form as it is marketed (e.g., NOLVADEX); and raloxifene hydrochloride can be sold by EVISTA. Fulvestrant can be formulated and sold as FASLODEX as disclosed in U.S. Patent No. 4,659,516. Combinations of the pharmaceutically active agents comprising antiestrogens of the present invention are particularly useful for treating estrogen receptor positive tumors (e.g., breast tumors). The term "anti-hypercalcemia" as used herein refers to a compound that can be used to treat hypercalcemia. Examples of anti-hypercalcemia agents include, but are not limited to, gallium nitrate (iii) hydrate; and disodium pamidronate. The term "anti-leukemia compound" as used herein includes, but is not limited to, Am-c, a pyrimidine analog, which is a deoxybenzoic 2,_α-hydroxyribose (arabose) derivative. Also included are hypoxanthine, 6_mercaptopurine (6_Μρ) and acid-filled Dundalabine. Let's... ‘,閗 你, you are a compound that inhibits or destroys DNA synthesis and causes cell death. Here + 丨 G things. Examples of antimetabolites include, but are not limited to, 6-mercaptopurine; cytarabine; fludarabine; fluorouracil; fluorouracil; capecitabine; raltitrexed; methotrexate; ; gemcitabine; gemcitabine hydrochloride; sulfur gas ring

, 丨1 雨布呤, hydroxyurea; DNA 144363.doc •83- 201032806 Demethylating agents, such as 5-azacitidine and decitabine; edarshasha and folic acid antagonists, such as (but not Limited to pemetrexed. Capecitabine can be administered, for example, in the form as it is marketed (e.g., under the tradename XEL(R) DA; and gemcitabine is administered as GEMZAR. The term "anti-proliferative antibody" as used herein includes, but is not limited to, bevacizumab (AVASTIN), rituximab (RITUXAN), pR〇64553 (anti-CD40), and 2C4 antibodies. By antibody is meant, for example, an intact monoclonal antibody, a multi-antibody from a multi-specific antibody formed by an intact antibody, and an antibody sheet #' as long as it exhibits the desired biological activity. The term "apoptosis-inducing agent" as used herein relates to a compound which induces a series of normal events in a cell to cause cell death. The apoptosis inducing agent of the present invention selectively induces an apoptotic protein X1Api χ linked to a mammalian inhibitor. The apoptosis inducing agent of the present invention can downregulate BcL_xL. Examples of apoptosis inducing agents include, but are not limited to, ethanol, 2_[[3_(2,3-diphenoxy)propyl]amino]-(9C1); gambogic acid; Enbeline, which is also known As 2,5-cyclohexadiene_丨, 4_dione, 2,5-dihydroxy_3_undecyl and dioxane. The term rAT1 receptor antagonist as used herein includes, but is not limited to, agents such as DIOVAN. The term "aurora kinase inhibitor" as used herein relates to a compound that targets, decreases or inhibits the late phase of the cell cycle from the G2/M checkpoint to the mitotic checkpoint and late mitosis. An example of an Aurora kinase inhibitor includes, but is not limited to, Dinuclear 2, which is also known as the indoleamine, hydrazine, _ [1-(3- gas-4-fluorophenyl)-4-cyano-1? - »比唑_5_基]_ν,Ν-二曱基_ 144363.d〇< -84 - 201032806 (9CI) ° The term "aromatase inhibitor" as used herein relates to inhibiting estrogen production (ie The compounds of the androstenedione and testosterone are converted to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially armetame, exemestane, and formestane, and in particular non-steroids, especially • amine lutimidate, rogamine (roglethimide), ph bilu Mitt, Trilostat, Testosterone, Ketokonazole, Voltux, Fructus, Anastrozole and Letrozole. Exemestane is sold as AROMASIN; fulmes are sold as LENTARON; famotazole is sold as AFEMA; anastrozole is sold as ARIMIDEX; letrozole is sold as FEMARA or FEMAR; and amine lutite Sold by ORIMETEN. Combinations of pharmaceutically active agents comprising an aromatase inhibitor of the present invention are particularly useful for treating hormone receptor positive tumors (e.g., breast tumors). The term "biological response modifier" as used herein includes, but is not limited to, lymphokines or interferons (e.g., interferon gamma). The term "bisphosphonic acid compound" as used herein includes, but is not limited to, itraphosphine zero acid, phosphinic acid, tiludronic acid, pamidronic acid, alendronate, ibandronic acid, risedronate, and azole. Phosphonic acid. "Itrexine acid" can be administered, for example, in the form of a commercial form (for example, DIDRONEL); "phosphonate" can be administered by BONEFOS; "tilutinic acid" can be administered by SKELID; "Pamidronate "Acid" can be administered by AREDIA; "Alendronic acid" can be administered by FOSAMAX; "Ibandronic acid" can be administered by BONDRANAT; "Lesendronic acid" can be administered by ACTENEL; and "zoledronic acid" can be administered versus. 144363.doc -85- 201032806 The term "brutton tyrosine kinase (BTK) inhibitor" as used herein relates to a compound that targets, reduces or inhibits the development of human and murine B cells. An example of a BTK inhibitor includes, but is not limited to, aflatoxin. The term "calcinin inhibitor" as used herein relates to a compound which targets, decreases or inhibits the T cell activation pathway. One target of calcineurin inhibitors includes protein phosphatase 2B. Examples of calcineurin inhibitors include, but are not limited to, cypromethrin, which is also known as cyclopropanecarboxylic acid, 3-(2,2-diethylene-yl)-2,2-diindolyl, cyano (3) _Phenoxyphenyl)decyl ester (9C1); deltamethrin, also known as cyclopropanecarboxylic acid, 3_(2,2-dibromovinyl)_2,2-di@methyl-(S) -Cyano(3-phenoxyphenyl)decyl ester, (1R,3R)_(9Ci); fenvalerate _ 'which is also known as phenylacetic acid' 4-chloro-α_(ι_methylethyl) _, cyano (3 phenoxyphenyl) methyl ester (9C1); and tyrosine phosphorylation inhibitor 8. The term "CaM kinase II inhibitor" as used herein relates to a compound that targets, reduces or inhibits CaM kinase. CaM kinase constitutes a structurally related family of enzymes, including phosphorylase kinase, myosin light chain kinase and CaM. Kinase i-iv. It has been found that CaM kinase η (a best-acting multifunctional enzyme) is present in high concentrations in neuronal synapses and is present in certain regions of the brain where it can account for up to 2% of total protein content. In the vertebrate nervous system, CaM kinase II activation is associated with memory and learning processes. Targets for CaM kinase Π inhibitors include CaM kinase II. Examples of CaM kinase inhibitors include, but are not limited to, 5-isoquinoline sulfonic acid, 4-[(2S)-2-[(5-isoquinolinylindolyl)methylamino]-3- side Oxy-3-(4-phenyl-l-β-mercapto)propyl] styrene vinegar (9CI); and benzotrienamine, Ν-[2-[[[3-(4-) ) _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 144363.doc -86 - 201032806 The term "CD45 glutamate phosphatase inhibitor" as used herein relates to a compound which targets, decreases or inhibits the dephosphorylation of regulatory pTyr residues on Src family protein tyrosine kinases. It helps to treat a variety of inflammatory and immune disorders. An example of a CD45 tyrosine phosphatase inhibitor includes, but is not limited to, phosphonic acid, [[2-(4- phenoxy)·5-nitrophenyl]hydroxymethyl^ (9C1). The term "CDC25 phosphatase inhibitor" as used herein relates to a compound which detargets, reduces or inhibits the overexpression of cyclin-dependent kinases in tumors. An example of a CDC25 acidase inhibitor includes 1,4-naphthalene di-, 2,3-bis[(2-hydroxyethyl)thio]-(9(:1). The term "CHK kinase" as used herein. An inhibitor is a compound that targets, reduces or inhibits the overexpression of the anti-apoptotic protein Bel_2. The fe inhibitor of the kinase is CHK1A/slCHK2. One example of a CHK kinase inhibitor includes, but is not limited to, debromomannine. The term "a compound that targets/reduces protein or lipid kinase activity, or a protein or lipid phosphatase activity; or other anti-angiogenic compound" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and / or a sulphate kinase inhibitor or a lipid kinase inhibitor, for example: a compound that is dry, reduces or inhibits vascular endothelial growth factor receptor (VEGF) activity, such as a compound that targets, decreases or inhibits VEGF activity, particularly inhibition a compound of the VEGF receptor, such as, but not limited to, a 7H-pyrrolo[2,3-d]pyrimidine derivative, including {6[4_(4ethylpiperazine·indolyl)phenyl]_7Η·° And [2,3-d]pyrimidin-4-yl]-((R)-l-phenyl-ethyl)-amine; BAY 43-900 6; revealed in Essauline 144363.doc in w〇00/09495 • 87- 201032806 (isolcho line) compounds, such as (4 - tert-butyl-phenyl)-94-0 than bite-4-yl a thiol-isoquinolin-1-yl)-amine; and a compound that targets, decreases or inhibits platelet-derived growth factor receptor (PDGFR) activity, such as a compound that targets, decreases or inhibits PDGFR activity, particularly inhibits PDGF Receptor compounds, for example, N-phenyl-2-pyrimidine-amine derivatives, for example, imatinib, SU101, SU6668, and GFB-111; targeting, reducing or inhibiting fibroblast growth factor receptor (FGFR) An active compound; a compound that targets, decreases or inhibits insulin-like growth factor receptor 1 (IGF-1R) activity, such as a compound that targets, decreases or inhibits IGF-IR activity, particularly inhibits IGF-1R Compound of the body. Compounds include, but are not limited to, the compounds disclosed in WO 02/092599 and derivatives thereof, 4-amino-5-phenyl-7-cyclobutyl-pyrrolo[2,3-<1]pyrimidine derivatives ( a compound that targets, reduces or inhibits the activity of the Trk receptor tyrosine kinase family; a compound that targets, decreases or inhibits the activity of the Axl receptor tyrosine kinase family; ❿ targets, reduces or inhibits a compound that c-Met receptor activity; a compound that targets, decreases or inhibits the activity of the Ret receptor tyrosine kinase; a compound that targets, decreases or inhibits the activity of the Kit/SCFR receptor tyrosine kinase; targets, decreases or Compounds that inhibit the activity of the C-kit receptor tyrosine kinase- (part of the PDGFR family), such as compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, particularly the c-Kit receptor 144363.doc -88 - 201032806 compounds, for example, imatinib; compounds that dry, reduce or inhibit c-AM family members and their gene fusion products (eg, BCR-Abl kinase), such as targeting, reduction Or a compound that inhibits the activity of e-Abl family members and their gene fusion products For example, 'N-phenyl-2-pyrimidine-amine derivatives, for example, imatinib, PD180970, AG957 'NSC 68041 0 or PD 1 73955 'BMS-354825 from Parke Davis; to direct, reduce or inhibit the activity of Compounds: members of the protein kinase 〇C (PKC) and the Raf family of serine/threonine kinases, members of MEK, SRC, JAK, FAK, PDK, and Ras/MAPK family members, or PI(3) kinase family a member, or a member of the PI(3) kinase-associated kinase family, and/or a member of the cell cycle regulatory protein-dependent kinase family (CDK), and in particular, the staurosporine derivative disclosed in U.S. Patent No. 5,093,330 For example, militalin; examples of other compounds include, for example, UCN-01, Safingo, BAY 43-9006, bryostatin 1, perifosine; imofosin; RO 318220 and RO 320432 GO 6976 ; Isis ® 3 521 ; LY333 531/LY3 79196 ; Isoquinoline compounds, such as those disclosed in WO 00/09495; FTIs; PD184352 or QAN697, . P13K inhibitors; targeting, reducing or inhibiting proteins a compound of tyrosine kinase activity, such as Ima Tini mesylate (GLEEVEC); tyrosine phosphorylation inhibitor or pyrimidinyl benzoguanamine and its derivatives. The tyrosine phosphorylation inhibitor is preferably a low molecular weight (Mr < 1500) compound or a pharmaceutically acceptable salt thereof, especially a compound selected from the group consisting of benzalmalononitrile or S-aryl phenylpropane 144363.doc -89· 201032806 Nitrile or double matrix quinoline compound 'more specifically, any compound selected from the group consisting of tyrosine phosphorylation inhibitor 八23/汉〇-5 0810, AG 99, tyrosine phosphorylation inhibitor AG 213, tyrosine phosphorylation inhibitor AG 1748, tyrosine phosphorylation inhibitor AG 490, tyrosine phosphorylation inhibitor B44, tyrosine phosphorylation inhibitor B44 ( +) Enantiomer, urethane sulphate inhibitor AG 5 5 5, AG 494, sulphate sulphate inhibitor AG 556; AG957 and adafu; butyl (4-{[(2,5-) Di-phenylphenyl)methyl]amino}-benzoic acid adamantyl ester, NSC 680410, adaflufen); when referring to an antibody, it is intended to include intact monoclonal antibodies, nano antibodies, multiple antibodies, Multispecific antibodies and antibody fragments formed from at least 2 intact antibodies are as long as they exhibit the desired biological activity. The phrase "a compound that targets, decreases or inhibits protein or lipid phosphatase activity" as used herein includes, but is not limited to, inhibitors of phosphatase 1, phosphatase 2A, PTEN or CDC25, eg, ephedrine-8 or its derivatives Things. Short other anti-angiogenic compounds include, but are not limited to, steroids such as thalidomide (THALOMID) and TNP-470 for their activity, mechanism (e.g., independent of protein or lipid kinase inhibition). The phrase as used herein is not limited to retinoic acid, alpha expectation. "Compounds that induce cell division processes" include, but gamma- or delta-tocopherol or α_, 7_ or §_tocotrienol for the regulation of dye lignin walling inhibitors. Or alkalamine for observation, stupid and μ ΓΓ limited to soybeans, also known as ketone, 7-hydroxy-3-(4-hydroxyphenyl)_(9(:1);iso 144363.doc 201032806 Oromol and tyramine Acid phosphorylation inhibitor j.

The term "cyclooxygenase inhibitor" as used herein includes, but is not limited to, for example, a C〇X-2 inhibitor. The term "(: 〇12 inhibitor" as used herein relates to a compound that targets, reduces or inhibits the enzyme cox_2 (cyclooxygenase-2). Examples of COX-2 inhibitors include, but are not limited to, m• 丨哚 丨哚Hongyi amide, Bu (4-benzophenanthryl)_5_decyloxy_2_methyl_N_(2_phenylethyl)_(9ci) ·, 5-alkyl substituted 2-aryl Alkyl streptoacetic acid and derivatives, such as celecoxib (CELEBREX), rofecoxib (νιοχχ), etorizoxib, or 5-alkyl-2-arylaminophenylacetic acid, for example, 5-methylchloro-6-azinoamino)phenylacetic acid, luminaceta; and celecoxib. The term "CRAF kinase inhibitor" as used herein relates to a compound that targets, decreases or inhibits E-selectin and up-regulation of TNF-induced vascular adhesion molecules. Raf kinase plays an important role in cell division, proliferation and apoptosis as an extracellular signal-regulated kinase. One of the targets of cRAF kinase inhibitors includes, but is not limited to, RAF 1. Examples of cRAF kinase inhibitors include, but are not limited to, 3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodoindolin-2-one, and the present formamide, 3-(didecyl) Amino)_n-[3_[(4-carbyl benzhydryl)amino]-4-methylphenyl]-(9C1). The term "cyclin-dependent kinase inhibitor" as used herein relates to a compound that targets, decreases or inhibits cyclin-dependent kinases, which plays a role in mammalian cell cycle regulation. Cell cycle progression can be regulated by a series of sequential events, including cyclin-dependent kinases (Cdks) and activation and subsequent inactivation of cyclins. A group of Cdk can form a serine/threonine kinase of an active heteroal complex by binding to its regulatory subunit, cyclin 144363.doc -91 - 201032806. Examples of targeting of cell cycle protein-dependent kinase inhibitors include, but are not limited to, CDK, AHR, CDK1, CDK2, CDK5, CDK4/6, GSK3beta, and ERK. Examples of cyclin-dependent kinase inhibitors include, but are not limited to, N9-isopropyl-ornomostar; Oromol; Pulvanox 6, also known as benzoic acid, 2-gas-4-[ [2-[[(1 ))-1-(yl)methyl)_2-mercaptopropyl]amino]-9-(1-methylethyl)-9H-indol-6-yl]amino ]- · (9CI), cyclin-dependent kinase; ingot jade red, which is also known as 2h_〇弓丨«多-2-糖|' 3-(1,3-dihydro-3-o-oxyl- 2H-吲哚-2-ylidene)-1,3-di▲ Hydrogen_(9CI); Ken Baolong, which is also known as 吲哚[3 24^] 笨丙氮卓_ 6(5H)-_ ' 9-Bromo-7,12-dihydro-(9CI); Pulvanox A, which is also known as 1-butanol '2-[[6-[(3-phenylphenyl)amino]-9-( 1-mercaptoethyl)_9H-indole-2-yl]amino]methyl-, (2R)-(9CI); and indirubin-3,-monoterpene. The term "cysteine protease inhibitor" as used herein relates to a compound which coarsens, reduces or inhibits cysteine protease, which plays an important role in mammalian cell renewal and apoptosis. Cysteine protease inhibitor

An example of which includes, but is not limited to, 4-morpholinium amide, N-[(lS)-3-fluoro-2_Q pendant oxy-1-(2-phenylethyl)propyl]amino]_2_ Side oxy-丨-(phenylphenyl)ethyl]-(9C1). The term "DNA intercalator" as used herein relates to a compound which binds DNA and inhibits DNA, RNA and protein synthesis. Examples of 〇να intercalators include, but are not limited to, pucamycin and dactinomycin. The term "DNA bond cleavage agent" as used herein relates to a compound which causes DNA bond division and inhibits DNA synthesis, inhibits RNA and protein synthesis. 144363.doc -92· 201032806 One example of a DNA strand breakage agent includes, but is not limited to, bleomycin. The term "E3 ligase inhibitor" as used herein relates to a compound that targets to reduce or inhibit E3 ligase, which inhibits ubiquitination.

The transfer 'marks its degradation in the proteasome. Examples of E3 ligase inhibitors include, but are not limited to, N-((3,3,3_three gas, three I methyl W W

amine. S. The term "EDG binder" as used herein includes, but is not limited to, an immunosuppressive agent that controls lymphocyte recirculation, such as FTY72. °

The term "endocrine hormone" as used herein relates to a compound which causes androgen to be inhibited by a major application to the pituitary gland (net effect is a decrease in testosterone to a cleavage level). In females, ovarian estrogen and androgen synthesis are inhibited. An example of an endocrine hormone includes, but is not limited to, leuco = forest and megestrol acetate. The term "farnesyltransferase inhibitor" as used herein relates to a compound that targets, decreases or inhibits a Ras protein, which is normally abnormally active in cancer. One target of a guanyltransferase inhibitor includes, but is not limited to, RAS. Examples of farnesyltransferase inhibitors include, but are not limited to, a-hydroxyfarnesylphosphonic acid; butyric acid, 2-[[(2S)-2-[[(2S,3S)-2-[[(2R) -2.Amino-3-mercaptopropyl]amino]-3-decylpentyl]oxy] oxo_3_phenylpropyl]amino]-4-(methyl fluorenyl) )-,1·methylethyl ester, (2s)_(9ci); and oxytetracycline A. The term "Flk-1 kinase inhibitor" as used herein relates to a compound which targets, decreases or inhibits the activity of Flk-1 taurokinase. One target of Fik-1 kinase inhibitors includes, but is not limited to, KDR. Examples of Flk-1 kinase inhibitor 144363.doc • 93· 201032806 include, but are not limited to, 2-propenylamine, 2-cyano-3-[4-hydroxy-3,5-bis(1-methylethyl) Phenyl]_^^_(3_phenylpropyl)_, (2e)_(9ci). The phrase "a compound which targets, decreases or inhibits Flt_3S" as used herein includes, but is not limited to, compounds, proteins or antibodies that inhibit Fh-3, for example, N-benzimidyl-streptavidin, mitoxantrone Lin, sclerotin derivatives, SU11248 and MLN518. The term "genacillin antagonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is disclosed in U.S. Patent No. 4,1,274 and sold as Z.LADEX. Abaric can be formulated as disclosed in, for example, U.S. Patent No. 5,843,9,1. The term "glycogen synthase kinase_3 (GSK3) inhibitor" as used herein relates to a compound which targets, reduces or inhibits glycogen synthase kinase_3 (GSK3). Glycogen synthase kinase_3 (GSK_3; tau protein kinase 丨), a highly conserved 'universal manifestation of serine/threonine protein kinase,' is involved in the signal transduction cascade of multiple cellular processes, a proven Protein kinases involved in a variety of cellular functions including protein synthesis, cell proliferation, cell division, microtubule assembly/disassembly, and apoptosis. An example of a GSK3 inhibitor includes, but is not limited to, indirubin-3, a single fat. The term "heparanase inhibitor" as used herein refers to a compound which targets, reduces or inhibits the degradation of heparin sulfate. The term includes, but is not limited to, ρι_88 ° as used herein, the phrase "compounds for the treatment of hematological malignancies" including, but not limited to, FMS-like tyrosine kinase inhibitors, for example, targeting, reducing or inhibiting FMS-like tyrosine Compounds that are active at the kinase receptor (Flt_3R); interfere with 144363.doc -94- 201032806, lbD-arabinofuranosine (ara_c), and alkaloids; and alk inhibitors such as 'targeting, reducing or inhibiting degenerative A compound of lymphoma kinase. The term "histone deacetylase (HDAC) inhibitor" as used herein relates to a compound which inhibits histone deacetylase and possesses anti-proliferative activity. This includes, but is not limited to, the compounds disclosed in WO 02/22577, especially N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1Η-indol-3-yl)ethyl) ]-Amino]methyl]phenyl]·2Ε-2-propenylamine, and N-hydroxy-3-[4-[[[2· ^ (2_methyl_1Η_吲哚_3_) )-Ethyl]-amino]methyl]phenyl]-2indole-2-propenylamine and a pharmaceutically acceptable salt thereof (LBH589). It further comprises cycloheptyl aniline hydroxamic acid (SAHA); [4_(2-amino-phenylaminocarbamimidyl)-benzyl]-carbamic acid pyridine _3_ decyl steryl ester and Derivatives; butyric acid, pyrrolidine, trichostatin A, oxavastatin, abciceptin, depsipeptide; debudexin and tricepsin. Other examples include debuddin; He toxin, which is also known as the ring [L-alaninyl _D_ propylamine 醯*_(aS, 2S)_a_amino side oxy group; epoxy ethene octyl-D- Amidoxime] (9ci); sodium phenylbutyrate, cycloheptyl bis-hydroxamic acid; and trichostatin. The phrase "corticosteroid-containing implant" as used herein includes, but is not limited to, agents such as, for example, skin relaxant and dexamethasone. The term "j_K B_a kinase inhibitor (IKK)" as used herein relates to a compound which targets, decreases or inhibits nf_kB. Examples of guanidine inhibitors include, but are not limited to, 2-acrylonitrile, 3-[(4- mercaptophenyl)sulfonyl]-, (2Ε)_ (9C1). The term "insulin receptor tyrosine kinase" as used herein. Inhibitors are 144363.doc-95-201032806 in a compound that modulates the activity of phospholipids inositol 3-kinase, microtubule-associated protein, and S6 kinase. Examples of insulin receptor tyrosine kinase inhibitors include, but are not limited to, hydroxy-2-naphthyldecylphosphonic acid. The term "c-Jun N-terminal kinase (JNK) kinase inhibitor" as used herein relates to a compound which is a dry, reduced or inhibited Jun N-terminal kinase. Jun N-terminal kinase (JNK), a protein kinase directed by serine, is involved in the acidification and activation of c-Jun and ATF2 and plays an important role in metabolism, growth, cell division and apoptosis. Targets for JNK kinase inhibitors include, but are not limited to, DNMT. Examples of JNK kinase inhibitors include, but are not limited to, pyrazolone and/or gallic acid epigallocatechin. The term "microtubule adhesive" as used herein refers to a compound that disrupts the microtubule network, which is important for cell function during mitosis and division. Examples of microtubule adhesives include, but are not limited to, vinblastine sulfate; vincristine sulfate; vindesine; vinorelbine; docetaxel; paclitaxel; vinorelbine; disc-shaped demodex; colchicine and epo And its derivatives, for example, epothilone B or a derivative thereof. Paclitaxel is sold as TAXOL; Docetaxel is sold as TAXOTERE; vinblastine sulfate is sold as VINBLASTIN R.P; and vincristine sulfate is sold as FARMISTIN. Also included are paclitaxel in the general form and paclitaxel in various dosage forms. Typical forms of paclitaxel include, but are not limited to, betaxolol hydrogenate. Various dosage forms of paclitaxel include, but are not limited to, albumin nanoparticle paclitaxel, ONXOL, CYTOTAX sold as ABRAXANE. A disc-shaped Molyde is obtained as disclosed in, for example, U.S. Patent No. 5,010,099. Also included are the epothilone derivatives, which are disclosed in U.S. Patent No. 144, 363. doc-96-201032806, No. 6,194,181, WO 98/10121, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Particularly preferred is Epothilone A and/or B^ The term "mitogenic protein (MAP) kinase-inhibitor" as used herein relates to a compound that targets, decreases or inhibits mitogen. Promoter • The cytokinin (MAP) kinase is a group of protein serine/threonine kinases that activate and mediate signal transduction from the cell surface to the nucleus in response to various extracellular stimuli. These kinases regulate a number of physiological and pathological cellular phenomena, including inflammation, apoptotic cell death, oncogenic transformation, tumor cell invasion, and metastasis. An example of a MAP kinase inhibitor includes, but is not limited to, benzenesulfonamide, N-[2-[[[3-(4-phenylphenyl)-2-propenyl]methyl]amino]methyl]phenyl ]·Ν-(2-|^-ylethyl)-4-methoxy-(9C1). The term "MDM2 inhibitor" as used herein relates to a compound that directs, reduces or inhibits the interaction of MDM2 with a p53 tumor suppressor. An example of an MDM2 inhibitor includes, but is not limited to, trans-4_iodine, 4'-boranyl-chalcone. The term "MEK inhibitor" as used herein relates to a compound which targets, decreases or inhibits the kinase activity of MAP kinase ' MEK. One of the target sites for MEK inhibitors includes, but is not limited to, ERK. Targets for MEK inhibitors include, but are not limited to, cyclin D1. An example of a MEK inhibitor includes, but is not limited to, succinonitrile, bis[amino[2-aminophenyl)thio]indenyl]-(9C1). The term "methionine aminopeptidase inhibitor" as used herein includes, but is not limited to, compounds that target, reduce or inhibit methionine aminopeptidase activity. A compound that targets, reduces or inhibits the activity of amidin aminopeptidase (Example 144363.doc • 97· 201032806) Benben or a derivative thereof. The term "MMP inhibitor" as used herein relates to a protease enzyme that targets, reduces or inhibits the selective catalysis of the hydrolysis of a polypeptide bond (including involvement in promoting tissue loss around the tumor and promoting tumor growth, angiogenesis and metastasis). A compound of the enzymes MMP-2 and MMP-9). One target of an MMP inhibitor includes, but is not limited to, a polypeptide deaminase. Examples of MMP inhibitors include, but are not limited to, payoff guanamine, also known as butyramine, N4-hydroxy-Nl-[(lS)-l-[[(2S)-2-(hydroxymethyl)- P-pyridinyl]carbonyl]-2-methylpropyl]-2-pentyl-, (2R)-(9CI); gallic acid-free hypotrophic catechin ester; collagen peptidomimetic And non-prime peptidomimetic inhibitors; four-cyclin derivatives, for example, the hydroxamic acid peptidomimetic inhibitor batimastat; and its orally bioavailable analogs, Marimastat, Promethrin He, Metestat, Neovastat, Tanomastat, TAA211, MMI270B or AAJ996. The term "monoclonal antibody" as used herein includes, but is not limited to, bevacizumab, temimumab and tocilizumab, and iodine I 131. Bevacizumab can be administered in a commercially available form (eg, AVASTIN); rituximab can be administered by MABTHERA; immozumab can be administered by ZEVULIN; and tosimizumab and iodine I 131 can be BEXXAR Cast. The term "NGFR tyrosine-kinase-inhibitor" as used herein relates to a compound that targets, decreases or inhibits nerve growth factor-dependent pl4 (Tuk tyrosine phosphorylation. NGFR tyrosine-kinase-inhibitor Target sites include, but are not limited to, FLK1, FAK, TrkA, and/or TrkC. Indirect target sites can inhibit RAF 1 expression. One example of NGFR tyrosine kinase inhibitors includes but 144363.doc -98- 201032806 is not limited to cool amine acids Phosphorylation inhibitor AG 879. The term "p38 MAP kinase inhibitor" as used herein relates to a compound which targets, decreases or inhibits p38-MAPK, a member of the ρ38_ΜΑρκ family of ΜΑΡΚ family members which are tyrosine and Phosphorylation of threonine residues - activating serine/threonine kinase. This kinase can be phosphorylated and activated by many cellular stresses and is believed to be involved in important cells such as apoptosis and inflammatory responses. Reaction Regulation. One example of a ρ38 ΜΑρ kinase inhibitor includes, but is not limited to, phenol, 4·[4_(4-fluorophenyl)5(4-pyridyl)_ m-imidazolyl-2-yl]-(9C1). An example package for SAPK2/P38 kinase inhibitors Including but not limited to benzoguanamine, 3-(dimethylamino)_N_[3_[(4-hydroxybenzylidenyl)amino]-4-fylphenyl]-(9C1). The term as used herein. P56 tyrosine kinase inhibitors are compounds that target, reduce or inhibit P56 tyrosine kinase, a p56 tyrosine kinase, a lymphocyte-specific src family of tyramine that is essential for tau cell development and activation.睃 kinase, a dry site of the p56 tyrosine kinase inhibitor, including but not limited to, the Lch Lck line is associated with the cytoplasmic domain of CD4, CD8, and the beta chain of the IL-2 receptor and is believed to be involved in tcr_mediated The earliest steps of τ-cell activation. Examples of 65 6-amino acid kinase inhibitors include, but are not limited to, squalane, which is also known as 2-nonanaldehyde, 9,10-dihydro-3-hydroxy-1. Methoxy-9,10-di-oxy-(9C1) and/or succinic acid acidification inhibitor 46. The term "PDGFR tyrosine kinase inhibitor" as used herein relates to targeting, reduction or inhibition. Compounds that are active in the C-kit receptor tyrosine kinase (part of the PDGFR family), such as targeting, reducing or inhibiting the activity of the c-Kit receptor tyrosine kinase family , especially the inhibition of c_Kit receptor 144363.doc -99· 201032806, PDGF plays an important role in cell proliferation, chemotaxis and normal cell survival as well as various disease states such as cancer, atherosclerosis and fibrotic diseases. The PDGF family consists of a dimeric subtype (pdgF-ΑΑ, PDGF-BB, PDGF-AB, PDGF-CC, and PDGF-DD) that binds to two receptor tyrosine kinases differently. Give play to its cellular effects. PDGFR-α and PDGFR-β have molecular masses of ~17〇 and 180 kDa, respectively. Examples of targets for PDGFR tyrosine kinase inhibitors include, but are not limited to, PDGFR, FLT3, and/or c-KIT. Examples of PDGFR tyrosine kinase inhibitors include, but are not limited to, tyrosine phosphorylation inhibitor AG 1296; tyrosine acidification inhibitor 9; 1,3-butadiene-1,1,3-tricarbonitrile, 2-Amino-4-(111-,indol-5-yl)-(9Cl); Imatinib and IRESSA. As used herein, the "lipositol 3-kinase inhibitor" is directed to a compound which targets, decreases or inhibits PI 3-kinase. PI 3_kinase activity has been shown to increase in response to § no-hormone and growth factor stimulation, including insulin, platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, colony-stimulating factor, and hepatocytes. Growth factors' and are involved in several processes related to cell growth and transformation? 1 3_Enzymatic activity. An example of a dry position of a fat-filled inositol 3-kinase inhibitor includes, but is not limited to, Pi3K. Examples of phospholipid inositol 3-kinase inhibitors include, but are not limited to, wortmannin, which is also known as 3H-furo[4,3,2-de] and [4'5-h]-2-benzo Pyran-3,6,9-trione, 11-(ethenyloxy)_ 1'61)'7,8,93,10,11,1113-octane-1-(methoxy fluorenyl) )-9&,111)-dimethyl_' US,6bR,9aS,llR,llbR)-(9CI); 8-phenyl-2-(morpholine-4-yl)-benzo-4-one, 4-(Trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyrodo_2_ 144363.doc •100- 201032806 Amine, 2_methyl-2-[4-(3 _methyl_2_sideoxy_8_quinoline_3_yl_2,3_diindole-mi. Sit and [4,5-c]啥淋_丨_基)_phenyl]_丙Nitrile and / or quercetin dihydrate. The term "phosphatase inhibitor" as used herein relates to a compound which targets, decreases or inhibits nitase. Phosphatase removes the phosphonium group and restores the protein to its original dephosphorylated state. Thus, the phosphorylation-dephosphorylation cycle can be considered a molecular "on" switch. Examples of phosphatase inhibitors include, but are not limited to, plaque acid; cantharidin; and L-leucine amide, N-[4-(2-carboxyvinyl)benzoyl]glycine-L- --glutamic acid thiol-, (E)-(9C1). ® The term "photodynamic therapy" as used herein refers to a therapy that uses some of the chemicals known to act as photosensitizers to treat or prevent cancer. Examples of photodynamic therapy include, but are not limited to, treatment with agents such as, for example, VISUDYNE and 卟 姆 um. The term "platinum agent" as used herein relates to a compound which contains platinum and which inhibits DNA synthesis by forming interchain and intrachain crosslinks of DNA molecules. Face agents include, but are not limited to, examples of carboplatin; cisplatin; oxaliplatin; cisplatin; satraplatin; and platinum agents such as ZD0473. Carboplatin can be administered, for example, in the form as it is marketed (e.g., CARBOPLAT); and oxaliplatin can be administered by ELOXATIN. The term "protein phosphatase inhibitor" as used herein relates to a compound which modulates, reduces or inhibits protein phosphatase. The term "PP1 or PP2 inhibitor" as used herein relates to a compound that directs, reduces or inhibits Ser/Thr protein phosphatase. Type I phosphatases (including ρρι) can be inhibited by two thermostable proteins called inhibitor-1 (1-1) and inhibitor 2 (1_2). These thermostable proteins are preferably phosphorylase kinase subunits Η 144363.doc 101 · 201032806 phosphatase dephosphorylation enzymes, which separate phosphatase into spontaneous activity (PP2A), CA2+-dependent (PP2B) and Mg2+-dependent (PP2C) category. Examples of PP1 and PP2A inhibitors include, but are not limited to, cantharidin and/or plaque. The term "tyrosine phosphatase inhibitor" as used herein relates to a newer member of the protein tyrosine acid phytase (PTP) linase family of compounds that target, reduce or inhibit tyrosine phosphatase. . These phosphate groups can be removed from the phosphorylated tyrosine residues of the protein. PTP exhibits a variety of structural features and plays an important role in regulating cell proliferation, division, cell adhesion and movement, and cytoskeletal function. Examples of dry positions of the tyrosinase inhibitor include, but are not limited to, a test phosphatase (ALP), a heparanase, a PTPase, and/or a prostatic acid phosphatase. Examples of tyrosine phosphatase inhibitors include, but are not limited to, LP-bromotetrazide oxalate; furanone, 4-hydroxy-5-(hydroxymethyl)_3_(1-hydroxyxetyl)_, (5R)_(9C1), and benzylphosphonic acid. The term "PKC inhibitor" as used herein relates to a compound which targets, decreases or inhibits protein kinase C and its isozyme. Protein kinase c (PKC), a ubiquitin phospholipid-dependent enzyme, is involved in signal transduction associated with cell proliferation, division, and apoptosis. Examples of the (four) position of the PKC inhibitor include, but are not limited to, MAPK and/or 4B. Examples of PKC inhibitors include, but are not limited to, 1-H-pyrrolo-2 5 -open 2,5-ketone, %[1-[3-(dimethylamino)propyl]- 1H-indole- 3-yl]_4_(1Η_吲哚_3_yl η·Guang bis-indenyl maleimine m alcohol, which is called amine _, (2S'3R'4E)-(9CI); The bacteriocin is called 9, m methoxy _ 1 Η, 9 Η ·: (4) and [1, 2, 3 3 3,, 2, 1, 1, and [3,4·· 144363.doc 201032806 and dinitrogen Heterocyclic purinetetraen-1-one, 2,3,1〇,11,12,13-hexahydro-1?-methoxy- 9-methyl-11-(decylamino)-, (9S , l〇R, llR, l3R)-(9CI); tyrosine phosphorylation inhibitor 51; and hypericin, also known as phenoline and [1,10,9,8_〇?91^ ]茈-7,14-dioxin, 1,3,4,6,8,13-hexahydroxy_1()11_ • dimethyl-, stereoisomer (6CI, 7CI, 8CI, 9CI). The term "PKC δ kinase inhibitor" as used herein relates to a compound which targets, reduces or inhibits the δ isozyme of PKC. The δ isozyme is a PKC isozyme and has a Ca 2+ dependency. An example of a delta kinase inhibitor includes, but is not limited to, crude carp, which is also known as 2-propenone, 1-[6-[ (3-Ethyl-2,4,6-trihydroxy-5-methylphenyl)indenyl]_5,7-dihydroxy-2,2-dimethyl-2-indole-1-benzopyran_ 8_基]_3_phenyl...(2Ε)_ (9CI). The term "polyamine synthesis inhibitor" as used herein relates to a compound which targets, reduces or inhibits polyamine quinone. Polyamine concentrate and fine Amine plays a crucial role in cell proliferation, but its exact mechanism of action is still unclear. The polyamine homeostasis in tumor cells is altered by the increase in biosynthetic enzyme activity and the increase in Iamine pool. Examples of synthetic inhibitors include, but are not limited to, DMFO, which is also known as (i)_2-difluorodecylguanine; Ni, Ν12-diethylspermine 4HC1. The term "proteosome inhibitor" as used herein relates to a target. Examples of dry, reduced or inhibited protein bodies. Examples of dry positions of proteosome inhibitors include, but are not limited to, 0(2)(-)-NADPH-producing oxidases, NF-κΒ and/or fascinating transferases, Geranylgeranyltransferase I. Examples of proteosome inhibitors include, but are not limited to, aclarinin A; gliotoxin; ps_341; 144363.doc-103-201032806 MLN 341; Antibiotic; or Vicard. The term "PTP1B inhibitor" as used herein relates to a compound that targets, decreases or inhibits PTP 1B, a protein tyrosine kinase inhibitor. One example of a PTP1B inhibitor includes, but is not limited to, L- Amine leucine, N-[4-(2-carboxyvinyl)benzimidyl]glycidyl-L-α-glutamic acid-, (E)-(9C1). The term "protein tyrosine kinase inhibitor" as used herein relates to a compound which targets, decreases or inhibits protein tyrosine kinase. Protein tyrosine kinase (PTK) plays a key role in regulating cell proliferation, division, metabolism, migration and survival. These can be divided into receptor type PTK and non-receptor type PTK. Receptor type PTK contains a single polypeptide chain with a transmembrane segment. The extracellular end of this segment contains a high affinity ligand binding domain, while the cytoplasmic end contains a catalytic core and regulatory sequences. Examples of targets for tyrosine kinase inhibitors include, but are not limited to, ERK1, ERK2, Bruton's tyrosine kinase (Btk), JAK2, ERK%, PDGFR, and/or FLT3. Examples of indirect target sites include, but are not limited to, TNFa, NO, PGE2, IRAK, iNOS, ICAM-1 and/or E-selectin. Examples of tyrosine kinase inhibitors include, but are not limited to, tyrosine phosphorylation inhibitor AG 126; tyrosine phosphorylation inhibitor Ag 1288; tyrosine phosphorylation inhibitor Ag 1295; geldanamycin; Savonoids. Non-receptor glutamine kinases include members of the Src, Tec, JAK, Fes, Abl, FAK, Csk, and Syk families. These lines are located within the cytoplasm as well as within the nucleus. It exhibits unique kinase regulation, substrate phosphorylation and function. Several human diseases are also associated with these kinase disorders. 144363.doc •104- 201032806 The term "SRC family of tyrosine kinase inhibitors" as used herein relates to a compound which targets, decreases or inhibits SRC. Examples of SRc family tyrosine kinase inhibitors include, but are not limited to, PP1, which is also known as ΐΗββ-pyrazolo[3,4-d](tetra)·4-amine, ... succinylethyl) 3 (1 naphthyl) )))) and ΡΡ2 'which is also known as 1Η_. Butazolo[3 4_d] ridiculidine iodide, 3·^_ phenylphenyl)-1-(1,1-didecylethyl)_(9CI).

The term "Syk tyrosine kinase inhibitor" as used herein relates to a compound which targets, decreases or inhibits Syk. Examples of no-positions of Syk tyrosine kinase inhibitors include, but are not limited to, 8 exo, 81^3, and/or STAT5. An example of a tyrosine kinase inhibitor includes, but is not limited to, tetrahydrotranspurin (PiCeatann®), which is also known as 1,2-benzenediol, 4-[(lE)_2_(3,5-dihydroxyl) Phenyl)ethidyl]-(9CI). The term "janus (JAK_2 and/or JAK_3) tyrosine kinase inhibitor" as used herein relates to a compound that targets, decreases or inhibits janus tyrosine kinase. The janus tyrosine kinase inhibitor has been shown to have anti-leukemia agents with antithrombotic, anti-allergic and immunosuppressive properties. The dry sites of JAK_2 and/or JAK-3 valine kinase inhibitors include, but are not limited to, JAK3, STAT3. Examples of JAK-2 and/or JAK-3 tyrosine kinase inhibitor inducing stems including, but not limited to, CDKh JAK-2 and/or JAK-3 tyrosine kinase inhibitors include, but are not limited to, tyrosine phosphorylation Inhibitor AG 490; and 2-naphthylethenyl ketone. The term "inhibitor of a Ras oncogenic subtype" as used herein includes, but is not limited to, H_Ras, K-Ras or N-Ras as used herein, and refers to a compound that targets, decreases or inhibits the carcinogenic activity of Ras, for example, farnesyl transfer. Enzyme 144363.doc • 105- 201032806 Inhibitor (FTI), for example, l-744832, DK8G557 or R1 15777 (ZARNESTRA). The term "retinoid" as used herein refers to a compound which targets, decreases or inhibits a retinoid-dependent receptor. Examples include, but are not limited to, isotret & acid and retinoic acid. The term "ribonucleotide reductase inhibitor" as used herein includes, but is not limited to, pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or ara-C; 6-thioguanine; 5-FU; carat Qubin; 6_酼基嘌呤, especially in combination with ara-C against ALL; and/or pentastatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H_isoindole 丨, 3_di-derivatives such as PL-1, PL-2, PL-3, PL-4, PL -5, PL-6, PL-7 or PL-8. See Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994). The term "RNA polymerase Η elongation inhibitor" as used herein relates to a compound that targets, reduces or inhibits insulin-stimulated nuclei and cytosolic p70S6 kinase in CHO cells; compounds that target, reduce or inhibit transcription of rna polymerase II; RNA polymerase π transcription can be dependent on casein kinase II, and stem to a compound that reduces or inhibits rupture of bovine oocyte nuclear vesicles. An example of an RNA polymerase π elongation inhibitor includes, but is not limited to, 5,6-dichloro-indole-β-D-ribofuranosylbenzimidazole. The term "S-adenosylmethionine decarboxylase inhibitor" as used herein includes, but is not limited to, the compounds disclosed in U.S. Patent No. 5,461,076. The term "serine/threonine kinase inhibitor" as used herein relates to a compound which inhibits serine/threonine kinase. Serine/threonine kinase 144363.doc 201032806 One example of a target of an inhibitor includes, but is not limited to, dsRNA-dependent protein kinase (PKR). Examples of targets for binding between serine/threonine kinase inhibitors include, but are not limited to, MCP-1, NF-κΒ, elF2a, COX2, RANTES, IL8, CYP2A5, IGF-1, CYP2B1, CYP2B2, CYP2H1, ALAS- 1. HIF-1, erythropoietin and/or CYP1A1. An example of a serine/threonine kinase inhibitor includes, but is not limited to, 2-aminoindole, also known as 1H-indol-2-amine (9C1). The term "somatostatin receptor antagonist" as used herein includes, but is not limited to, Φ agents that target, treat or inhibit somatostatin receptors, such as octreoride and SOM230. The term "sterol biosynthesis inhibitor" as used herein relates to a compound which inhibits sterol biosynthesis such as cholesterol. Examples of targets for sterol biosynthesis inhibitors include, but are not limited to, squalene epoxidase and CYP2D6. An example of a sterol biosynthesis inhibitor includes, but is not limited to, terbinafine. The term "telomerase inhibitor" as used herein includes, but is not limited to, a compound that targets, reduces or inhibits telomerase activity. Compounds which target, reduce or inhibit telomerase activity are, in particular, compounds which inhibit the telomerase receptor, for example, • Tromestatin. The term "topoisomerase inhibitor" includes topoisomerase I inhibitors and topoisomerase II inhibitors. Examples of topoisomerase I inhibitors include, but are not limited to, topotecan, gematidine, irinotecan, camptothecin and the like, 9-nitrocamptothecin, and macromolecular camptothecin conjugates PNU-166148 (Compound A1 of WO 99/17804); 10-hydroxycamptothecin acetate; Relying on 144363.doc •107- 201032806 Poor; Idarubicin Hydrochloride; Irinotecan Hydrogenate; Poscoside; topotecan hydrochloride; doxorubicin; epirubicin hydrochloride; mitoxantrone hydrochloride; and daunorubicin hydrogenate. Irinotecan can be administered, for example, in the form as it is marketed (e.g., the trademark CAMPTOSAR). Topotecan can be administered, for example, in the form as it is marketed (e.g., under the trademark -HYCAMTIN). The term "topoisomerase purine inhibitor" as used herein includes, but is not limited to, anthracyclines such as doxorubicin (including liposome formulations, eg, CAELYX), daunorubicin (including liposome formulations, For example, DAUNOSOME), epirubicin, idarubicin and nepyridamole, mitoxantrone and loxoprost; and podophillotoxine-based etoposide are popular for tenipoper. Reliance is sold as ETOPOPHOS; teniposide is sold as VM 26-BRISTOL; doxorubicin is sold as ADRIBLASTIN or ADRIAMYCIN; epirubicin is sold as FARMORUBICIN; Idaby is sold as ZAVEDOS; The tray is sold as NOVANTRON. The phrase "tumor cell destruction method" refers to a method such as ionizing radiation. The term "ionizing radiation" as referred to above and hereinafter means ionizing radiation occurring in the form of electromagnetic rays such as X-rays and ❹ γ rays or particles such as α, β and γ particles. Ionizing radiation is provided in, but not limited to, radiation therapy and is well known in the art. See Heilman, Cancer, 4th ed., Vol. 1, Devita et al., ed., pp. 248-275 (1993). The phrase "monoclonal antibody to VEGF or VEGFR" as used herein includes, but is not limited to, the compounds disclosed in WO 98/35958 (for example, 1-(4-cyclophenylamino)-4-(4-" A pyridazine or a pharmaceutically acceptable salt thereof, for example, 144363.doc-108-201032806 succinate) or as disclosed in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/1 1223, WO 00/27819 and the compounds of European Patent 〇 769 947; they are by Prewett et al., Cawcer Λα, Vol. 59, pp. 5209-5218 (1999); Yuan et al. /Voc dead - , 93, pp. 14765-14770 (1996); Zhu et al., vol. 58, pp. 3209-3214 (1998);

Mordenti et al., Tox/co/ Ραί/ζο/, Vol. 27, No. 1, pp. 14-21 (1999); as described in WO 00/37502 and WO 94/10202; # ANGIOSTATIN, O 'Reilly et al., Ce//, vol. 79, pp. 315-328 (1994); ENDOSTATIN, O'Reilly et al., Ce//, vol. 88, pp. 277-285 (1997) Said; o-aminobenzamide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibody or anti-VEGF receptor antibody, for example, rhuMAb and RHUFab; VEGF aptamer (eg, Sodium pegatanibide; FLT-4 inhibitor, FLT-3 inhibitor, VEGFR-2 IgGl antibody, Angiozyme (RPI 4610) and Avastin. W The term "VEGFR tyrosine kinase inhibitor" as used herein relates to a compound which targets, reduces and/or inhibits known angiogenic growth factors and cytokines involved in normal and pathological angiogenesis. VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D) and their corresponding receptor tyrosine kinases [VEGFR-1 (Flt-1), VEGFR-2 (Flk-Ι, KDR), and VEGFR-3 (Flt-4) plays a vital and indispensable role in regulating angiogenesis and lymphangiogenesis processes. An example of a VEGFR tyrosine kinase inhibitor includes, but is not limited to, 3-(4-di-144363.doc-109-201032806 methylaminobenzylidene)-2-indolone. The term "RANKL inhibitor" as used herein relates to a compound which targets, decreases or inhibits the RANK/RANKL pathway. RANK inhibitors prevent osteoclast-mediated bone loss in a number of conditions, including osteoporosis, treatment-induced bone loss (bone loss due to glucocorticoid therapy and immunosuppression), rheumatoid joints Inflammation, bone metastasis and multiple myeloma. An example of a RANKL inhibitor includes, but is not limited to, denosumab. The following is only to illustrate by way of example.实例 Example 1 Two cancer-derived cell lines (BT474 and MDA-MB-231) were used. These are human breast cancer cell lines. Such cell lines are commercially available from the American Type Culture Collection (ATCC). BT474 cells were maintained in Hybri-Care medium (ATCC) supplemented with 10% v/v fetal bovine serum and 2 mM L-glutamine. MDB-MB-231 cells were grown in RPMI 1640 culture medium (Animed, Allschwil, Switzerland) supplemented with 10% v/v fetal bovine serum and 2 mM L- faceamine. The medium was supplemented with 1 μg/ml Penicillin/Keymycin and the cells were maintained at 37 ° C in 5% CO 2 . After the cells began to divide and change the medium, the cells of the reserve culture were seeded on the cell plate at a density of 3.3χ104 cells/cm2 (BT474) and 1.2χ104 cells/cm2 (MDB-MB-231) and at 37 ° C and Incubate for 48 hours at 5% C02 and then treat with DMSO vehicle, 20 nM everolimus (RAD001) and/or various concentrations of AUY922 (compound 1) for 24 hours. To prepare cell lysates, the plates were washed once with ice containing 144 mM phenylmethylsulfonate (PMSF) 144363.doc -110· 201032806 cold phosphor buffered saline (PBS) and ice-cold extraction buffer (50 mM) Hepes pH 7.4, 150 mM NaCl, 25 mM β-glycerophosphate, 25 mM NaF, 5 mM EGTA, 1 mM EDTA, 15 mM PPi, 2 mM sodium orthoformate, 10 mM La sodium, bright aprotinin (10 Micrograms/ml), peptidase (10 μg/ml), 1 mM DTT and 1 mM PMSF) were washed once. The cells were extracted in the same buffer containing 1% NP-40. The extracts were homogenized by centrifugation, aliquoting and freezing at -80 °C. Protein concentration was determined by means of the BCA protein assay (Pierce, Rockford, IL, USA). φ 20 μg of cell extract was resolved by 12% denatured sodium lauryl sulfate polyacrylamide gel (SDS-PAGE) electrophoresis and transferred to a polytetrafluoroethylene filter by wet blotting (1 hour at Detection at 250 mA) and overnight at 4 °C with the following primary antibody: Anti-phosphate-Akt (Ser473) obtained from DAKO (Glostrup, Denmark) and diluted in PBS, 0.5% v/v Tween (pure line 14- 05; 1:2000). Anti-phospho-Akt (T308) 获得 (Catalog No. 9275; 1:1000) obtained from Cell Signaling Technology (Beverly, MA, USA) and diluted in PBS, 0.1% v/v Tween. Anti-Akt (Catalog No. 1085-1; 1:5000) obtained from Epitomics (Burlingame, CA, USA) and diluted in PBS, 0.50/〇.v/v Tween. Anti-actin obtained from Chemicon (Billerica, MA, USA) and diluted in PBS, 0.1% v/v Tween (catalog number MAB1501; 1:20,000) ° after incubation with appropriate primary antibody (above), Horseradish peroxidase-conjugated anti-mouse or anti-rabbit immunoglobulin and intensive chemical fluorescein 144363.doc 201032806 Light agent (ECL Plus kit) were used to expose the decorative protein and use Quantity 〇 to software ( Bio-Rad, Munich, Germany) Quantitative. Example 2

Figure 1 shows the comparison of everolimus (RAD001) and everolimus (rad〇〇1) with compound I ((R)-2-amino-7-[2-(6-methoxy-) _2 _ _ _ phenyl _ _ 4 曱 -7 -7,8-dihydro-6H-" than pyridine[4,3-d]pyrimidin-5-one) in the presence of BT474 breast tumor cells The degree of acidification of the AKT. Inhibition of mTOR with radooi activates Akt in tumor cells (O'ReUiy et al., 2〇〇6). Western point collapse analysis demonstrated that the levels of phosphorylated AKT (p_AKT (S473) and P-AKT (T3〇8)) were observed to increase in bt_474 cells treated with 20 nM RAD001 compared to untreated controls. When using 5〇_1〇〇nM compound I ((R)-2-amino-7-[2-(6-methoxyl-But-2-yl)__styl]_4_methyl_7 , 8 · Dihydro-611-° than the bite [4,3-(1] ring. Ding-5-net) treatment of these cells, eight {^ bowl acidification ((P-AKT (S473) and P- AKT(T308)) was reduced. Adding 20 nM RAD001 in the presence of 50-100 nM Compound I did not cause AKT deacidification (P-AKT (S473) and P_AKT (T3〇8)). AKT content was affected by any The effect of the treatment was not significant. Actin was used to demonstrate equal protein loading on each path of the Western analysis of the breakout. Example 3 Figure 2 shows the relationship between everolimus (RAD001) and everolimus (RAD001). Compound I ((R)-2-amino-7-[2-(6-decyloxy-pyridin-2-yl)-phenyl]-4-indolyl-7,8-dihydro-6H-pyridine The degree of AKT phosphorylation in MDA-MB-23 1 breast tumor cells in the presence of a combination of [4,3-d]pyrimidin-5-one) has demonstrated that inhibition of mTOR by RAD001 activates Akt 144363 in tumor cells. Doc-112-201032806 (O'Reilly et al., 2006). Western point collapse analysis demonstrated that phosphorylated AKT (P-AKT (S473) content was observed in MDA-MB-23 1 cells treated with 20 nM RAD001 Increased in untreated controls. When these cells were treated with 50-1 00 nM Compound I, AKT phosphorylation (P-AKT (S473)) was reduced " less. At 50-100 nM Compound I (( R)-2-Amino-7-[2-(6-decyloxy-pyridin-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido[ In the presence of 4,3-d]pyrimidin-5-one), the addition of 20 nM RAD001 did not result in an increase in AKT phosphorylation at the amino acid residue T308. The AKT content was 100 nM compound I Φ ((R)-2 -amino-7-[2-(6-decyloxypyridin-2-yl)-phenyl]-4-methyl-7,8-dihydro-6Η-pyrido[4,3-d] Pyrimidine-5-one) was slightly decreased in the presence of this, consistent with the fact that the AKT Hsp90 guest protein was used. Actin was used to demonstrate that the protein load was equal on each path of the Western point collapse analysis. Description Figure 1 shows the degree of Akt phosphorylation in BT474 breast tumor cells in the presence of everolimus (RAD001) and everolimus (RAD001) in combination with Compound I; and ® Figure 2 shows in everolimus (Fig. 2) The degree of AKT phosphorylation in MDA-MB-231 breast tumor cells in the presence of RAD001) and everolimus (RAD001) in combination with Compound I. 144363.doc -113-

Claims (1)

201032806 VII. Patent application scope: 1. A pharmaceutical combination comprising (a) a compound of formula (I) Hsp9 inhibitor compound Ra 0 (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein 1 is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) CVC6 alkoxy, (5) Mercaptan, (6) Ct-Ce thiol, (7) substituted or unsubstituted C-C6 alkyl, (8) amine or substituted amine, (9) substituted or unsubstituted aromatic a group, (10) a substituted or unsubstituted heteroaryl group, and (11) a substituted or unsubstituted heterocyclic group; R is selected from the group consisting of: (1) hydrogen, (2). substituted or not Substituting CrCe alkyl, (3) substituted or unsubstituted C2-C6 alkenyl, 144363.doc 201032806 (4) substituted or unsubstituted C2_c6 alkynyl, (5) substituted or unsubstituted ^7 ring-burning a group, (6) substituted or unsubstituted (: acyclic ring, (7) substituted or unsubstituted aryl, (8) substituted or unsubstituted heteroaryl, and (9) substituted or Unsubstituted heterocyclic group; Rb is selected from the group consisting of: Ο) substituted or unsubstituted C3_C7 cycloalkyl, (2) substituted or unsubstituted (^-cycloalkenyl, (3) Substituted or unsubstituted aryl, (4) a substituted or unsubstituted heteroaryl group, and (5) a substituted or unsubstituted heterocyclic group; and the limitation is that if a Ra-based amine group, Rb is not a phenyl group, a 4-alkylphenyl group, a 4-alkoxy group Base-phenyl, or 4-comonyl-phenyl, or a compound of formula (E): Wherein R3 is selected from the group consisting of methylaminocarbonyl ch3ch2nhc(=o)-, ethylaminocarbonylch3ch2nhc(=o)-, propylaminocarbonylch3ch2ch2nhc(=〇)-, or isopropylaminocarbonyl (ch3) 2chnhc(=o)-), R8 is selected from methyl, ethyl, isopropyl, bromo or chloro; and 144363.doc 201032806 R9 is -CHzNRWr11 or -NR1GR", wherein the substituted amino-NR1GRU system Morpholinyl, hexahydropyridyl, piperazinyl, pyrrolidinyl, ethylamino, isopropylamino, diethylamino, cyclohexylamino, cyclopentylamino, methoxyethyl Amino, hexahydropyridin-4-yl, N-ethinylpiperazinyl, N-methylβ-bottom D-methyl, methyl-terminated amino group, thiopental, sulfur. morpholinyl- Dioxide, 4-hydroxyethylhexahydropyridinyl or 4-hydroxyhexahydropyridyl, -CH2-, which is related to the ruthenium, the hexahydro port, the thiol group, the π ratio ® , ethylamino, isopropylamino, diethylamino, cyclohexylamino, cyclopentylamino, methoxyethylamino, hexahydropyridin-4-yl, Ν-B Is mercapto piperazinyl, hydrazine-methylpiperazinyl, decylsulfonylamino, sulfur? Linki, thiomorphinyl-dioxide, 4-ylethylethylhexahydro. Or a pharmaceutically acceptable salt or prodrug, and (b) an mTOR inhibitor, linked to a thiol or 4-aminohexahydro D group. 2. The pharmaceutical combination of claim 1, wherein the mTOR inhibitor is everolimus®, rapamycin, ascomycin, CCI-779, ABT578, SAR543, AP23573, AP23841, AZD08055 or • OSI027 . 3. The pharmaceutical combination of claim 1, wherein the mTOR inhibitor is a rapamycin derivative of the formula 144363.doc 201032806 RW$CH3 or c3_6 alkynyl, R.2 H or -CHrCHrOH, 3-hydroxy-2-(hydroxymethyl)-2-methyl-propenyl or tetrasal, and X-form=0, (H , H) or (Η, ΟΗ), the restriction is that when X system = 〇, r2 is not Η, and when 尺 2 is -CH2-CH2-OH, R4CH3. 4. The pharmaceutical combination according to claim 1, wherein the Hsp90 inhibitor is (R)_2-amino-7-[2-(2-fluoro-pyridyl-3-yl)-phenyl]_4_indenyl-7 , 8_ dihydro _611_ pyridine bite [4,3-d] ridicule. 5-ketone, (S)_2-amino-6-benzyl-7_[4-fluoro-2-(2-fluoropyridyl-3-ylphenyl)-4-methyl-7,8-di Hydrogen-6H-pyrido[4,3-d]pyrimidin-5-one' (1〇-2-amino]_7_[4_fluoro_2_(2_fluoro_11-pyridyl-3-yl)-benzene 4-methyl-7'8-dihydro-6H_pyrido[4,3-d]pyrimidin-5-one, (R)-2-amino-7-(2-bromo-4-fluoro- Phenyl)-6-[(S)-1-(4-methoxy-phenyl)ethyl]-4-indolyl-7,8-dihydro-6H-pyrido[4,3-d Pyrimidine _5-ketone, (R)_2-amino group _7_[2_(6-methoxy^pyridin-2-yl)-phenyl]-4-indolyl- 144363.doc 201032806 7,8- Dinitrogen-611-° ratio bite [4,3-(1] shouting 5-ketone, (R)-2_amino-7-[4·fluoro-2·(6·methoxy-port Bipyridin-2-yl)-phenyl]-4-methyl-7,8-di-rho-6-Η-ϋ ratio σ定弁[4,3 - d ]啸0定-5 - Brewing I ' 2_ Amino-7-[4_murine-2-(6-methoxy-p-but-2-yl)-phenyl]-4,6-di-methyl-7,8-dihydro-6H- Pyrido[4,3-d]pyrimidin-5-one, .2-amino-7-[4-gas-2-(2-gas-.pyr.-3-yl)-phenyl]-4 ,6-dimercapto-7,8-dipho-6 Η -σ ratio bite ^ and [4,3 - d ]°定-5 -嗣' 2-amino-7-[4-fluoro-2- (6-methoxyacridin-2-yl)phenyl]-4-methyl-oxime 7,8-di Hydropyrido[4,3-d]pyrimidin-5(6H)-one, 2-amino-7-[2-(6-methyllacyl-0-pyridyl-2-yl)-phenyl]- 4-mercapto-7,8_dihydro-6H-° ratio bite [4,3-d] mouth bite 5-ketone, (R)-2-amino-7-[4-fluoro-2-( 6-decyloxypyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6Η-. Compared with α, [4,3-d] is a bit of 5-ketone, 2-Amino-7-[4-Ga-2-(6-methoxy-°°Chin-2-yl)-phenyl]-4,6-dimethyl-7,8-di-mouse- 6 Η - ° ratio σ 弁 [4,3 - d ] ° 密〇定-5 -嗣, 2-amino-7-[2-(2-methoxypyridin-3-yl)-phenyl ]-4-methyl-7,8-® dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-(5,2'-difluoro-biphenyl -2-yl)-4-methyl-7,8-dihydro-6H-π ratio bite [4,3-(1]03⁄4 bite-5-one, 2-amino-7-(5-fluoro) -2'-trifluoromethoxy-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amine Base-7-[2-(2-a-cyclopyridin-3-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6Η-Π ratio bite [4, 3-(1) gnashing 5-ketone, 2-amino-7-[4- gas-2-(6-rat-0 to -3-yl)-phenyl]-4-mercapto-7 , 8_ 144363.doc 201032806 Dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2 - Base - 7-(4- gas-2-isoindole-yl-phenyl)-4-methyl-7,8-two mice_6H-D than bite and [4,3-(1] mouth bite- 5-branched 1,2-amino- 7-(5,3'-di-biphenyl-2-yl)-4-indolyl-7,8-dipho-6H-0 ratio σ determinate [4 , 3-<1] mouth. 5-butanone, 2-amino- 7-[2-(4- gas-.pyridin-3-yl)-4-a-phenyl]-4-indolyl-7,8-dihydro- 6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-(5,2'-di-d-3·-decyloxy-biphenyl-2-yl)-4- Methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-(5,4'-difluoro-2'-fluorenyl-linked Benz-2-yl)-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-(5-fluoro-2' -Methoxy-biphenyl-2-yl)-4-mercapto-7,8-diaza-6 Η-° is more dense than [4,3-d]. 5-butanone, 2-amino- 7-(4-gas-2 - ° succinyl-5-yl-phenyl)-4-methyl-7,8-dipho-611-° ratio bite And [4,3-d] ° 密定-5-ketone, 2-amino-7-[4- gas-2-(2-methyllacyl-. butyl-3-yl)-phenyl] 4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino--7-(5-gas-3'-methoxy-linked Phen-2-yl)-4-methyl-7,8-di-rho-6 Η6Η-Πϋβ定[4,3-<1] σ-唆-5-one, (R)-2-amino- 6-(3-Amino-propyl)-7-[4-gas-2-(6-decyloxy-α-pyridin-2-yl)-phenyl]-4-methyl-7,8- Dihydro-6Hd is more than pyridyl[4,3-d]pyrimidin-5-one, 2-amino-7-(4-ran-2-0-buty-3-yl-phenyl)-4-methyl -7,8-Dinitro-6H-° is more than a bite [4,3-d] mouth. Ding-5-ketone, 144363.doc -6- 201032806 2-Amino-M5,2'-difluoro-4'-indenyl-biphenyl iyl)_4_methyl_7,8-dihydro-611 -pyrido[4,3_d]pyrimidine-5-indole, 2-amino group small [4_fluoro-2·(1_methyl·1η_^4yl)phenyl]methanol-7,8-dihydro -6H-pyrido[4,3_d]pyrimidine%_, • 2_Amino_7-[4·Fluorine sal.4-yl)-styl]_4_ Methyl-7,8_2. Hydrogen-6H- D is bite and [4,3-d] mouth bite -5-_, 2-amino-mercapto-7-(5,2,3,-trifluoro-phenylene-2-yl) 7,8- Dichloro-6H-n ratio bite [4,3-d] mouth bite _5-ketone, 2-amino group small (2-bromo-4-fluoro-phenyl)_4•methyl_6_(2_A 2·morpholine·4_yl·propyl)-7,8-dihydro-6Η-pyrido[4,3_d]pyrimidinone, 2-amino group small (3'-didecylamino group _ 5|Lianqi·2_base) ice methyl hydrogen-6H-1* than 唆[4,3-d]" dense bite-5-_, 2-amino-7-[2-(2, 4-dimethoxy-pyridinium φ--5-yl)_4_fluoro-phenyl]·4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidinone 2_Amino-7_[4-fluoro_2-(5-methylindolyl-n-Bist 7,7-bran-3-yl)-phenyl]-4-indenyl-S-dihydro-6Η- »Bit and [4,3-d]pyrimidine _5-N, 2-Amino-7-(4-fluoro-2-pyrimidine_5- _ 4泰)-4-methyl-6·(2-indolyl-2-pyrine-4-yl-propyl)-7,8-two invites _6Μ ~ ° than bite [4,3-d ] 嗣 嗣, 2_amino group: [4- gas-2-(2-carbamimidyl] 33 phenyl) phenyl] _ 4 · methyl 6-(2-methyl-2-morpholine-4 - propyl-propyl bauxite-, , dihydro-6 Η-° ratio bite [4,3.31 shouting-5-ketone' ' 』 2-amino-7-(5-fluoro-31-methyl group, Phenyl)_"yl-2-pyrine-4-yl-propyl)-7^dihydro- _"" than bite and [4,y] squirting two 144363.doc 201032806 ketone, (R)-2 -amino-7-[4- gas-2-(4-decyloxy-5-methyl-[3⁄4°-di-2-yl)-phenyl]-4-methyl-7,8-dihydro -6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino- 7-(4- gas-2-'•f-amyl-3-yl-phenyl)-4-methyl- 7,8-two mice _ 6H-pyrido[4,3-d]pyrimidin-5-one, 5-(2,4-diyl-5-isopropyl-phenyl)-4-(4- Or oxazolidine-3-carboxylate or its pharmaceutically acceptable salt or prodrug. 5. A pharmaceutical combination comprising: (a) an Hsp 90 inhibitor of formula (III) Ra Ο Or a pharmaceutically acceptable salt or prodrug thereof, wherein the Ra is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) thiol, (4) CVC6 alkoxy, (5) thiol , 144363.doc 201032806 (6) Ci_C6 alkyl mercaptan, (7) substituted or unsubstituted Ci_C6 alkyl, (8) amine or substituted amine, (9) substituted or unsubstituted aryl, (1 〇) substituted or unsubstituted heteroaryl, and (11) substituted or unsubstituted heterocyclic group; R is hydrogen or substituted or unsubstituted C丨_c6 alkyl; R is hydrogen, burned Or an alkyl group; R6, R7, R8, and R9 are each independently selected from hydrogen, alkyl, alkoxy, decyl, substituted or unsubstituted aryl, and substituted or a group of unsubstituted heteroaryl groups; the restriction is that if Ra is an amine group and R6, R7, uldent 8 and R9 are all hydrogen, then R5 is not hydrogen, alkyl, alkoxy, or halo; Compound of formula (E): R3 is selected from the group consisting of decylaminocarbonyl ch3ch2nhc(=o)-, ethylaminocarbonylch3ch2nhc(=o)-, propylaminocarbonylch3ch2ch2nhc(=〇)-, or isopropylamine thiol (ch3) 2chnhc(=o)-) 'r8 is selected from methyl, ethyl, isopropyl, bromo, or gas; and 144363.doc 201032806 R9 is -CHaNRWR11 or -NR1%11, wherein substituted amino group-NR1 1 series linalyl, hexahydro-beta butyl group, bristle group, n-bite, ethylamino group, isopropylamino group, diethylamino group, cyclohexylamino group, cyclopentylamino group , methoxyethylamino, hexahydro. Bipyridin-4-yl, N-ethenyl, bottom, Qin, N-methylindolyl, methyl hydrazino, thiophenanyl, thiophene-based, dioxide, 4 a trans-base group, a pharmaceutically acceptable salt or prodrug thereof, and (b) an mTOR inhibitor, with a base group or a 4-hydroxyl hexahydrocarbyl group. 6. The pharmaceutical combination of claim 5, which comprises everolimus, rapamycin, ascomycin or a rapamycin derivative. 7. A pharmaceutical combination comprising: (a) an Hsp90 inhibitor which is (R)-2-amino- 7-[2-(2- gas-to-bit ratio-3-yl)-benzene Base]_4_methyl_7,8_dihydro-6Η-° ratio bite [4,3-d]0^bit-5-one, 4-mercapto-7,8-dihydro-6Η-pyrido[4,3-d]pyrimidine (R)-2-amino-7-[4-fluoro-2-(2-fluoro-7,8-dihydro-6H-° ratio °[4,3-d], a _5-_ , (R)-2_Amino-7_[4_fluoro_2_(6-methylindenyl) Methyl-7,8-dihydro-6H-pyrido[4,3_d]pyrimidin-5-one 144363.doc •10- 201032806 2-Amino- 7- [4-Ga-2-(6-methoxy) The base-σ ratio 唆-2-yl)-phenyl]-4,6-dimethyl-7,8-dipho-6 Η-^ is more than σ and [4,3 - d ] whistling.定-5 -嗣, 2-Amino-7-[4- gas-2·(2-乱_π比淀-3-yl)-phenyl]-4,6-diindenyl-7,8- Two rats - 6 Η -. σ σ 弁 [4,3 - d ] - 5 -嗣, • 2-amino-7-[4-fluoro-2-(6-methoxyacridin-2-yl)phenyl]-4 Methyl--7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one, 2-amino--7-[2-(6-methyllacyl-^ ratio 17 Qin- 2-yl)-phenyl]-4-methyl-7,8-dihydro- sigma-[4,3-d] oxime-5-one, 〇(R)-2-amino-7-[ 4-fluoro-2-(6-decyloxy)pyrazine-2-yl)-phenyl]-4-methyl-7,8-dihydro-6Η-pyridyl[4,3-d]pyrimidine -5-keto, 2-amino-7-[4-gas-2-(6-oxime-°°-qin-2-yl)-phenyl]-4,6-dimethyl-7, 8 - 2 rat - 6 Η - bite and [4,3 - d ] 〇 π -5 -5 - 嗣, 2-amino-7-[2-(2-methoxy-.pyridin-3- Base)-phenyl]-4-methyl-7,8-two winds 1 _ 6 Η -π ratio bite [4,3 - d ] 嘲-5 -阙, 2-amino-7-(5 , 2'-difluoro-biphenyl-2-yl)-4-mercapto-7,8-dihydro-6H-° than hydrazino[4,3-d] gnache-5-one, ® 2- Amino-7-(5-fluoro-2.-trifluoromethoxy-biphenyl-2-yl)-4-mercapto-7,8--murine-6 Η-111 is more than [4,3 · d ]. dense. -5 - copper, 2 -amino - 7_[2-(2-gas-吼-yttrium-3-yl)-4-oxo-phenyl]-4-indenyl-7,8-dihydro-6H-pyridine And [4,3-d]pyrimidin-5-one, 2-amino-7-[4- gas-2·(6-gas σ ratio. -3-yl)·phenyl] 4-methyl- 7,8_ Dichloro-6Η-σ ratio bite [4,3-d]0^17-but-5-one, 2-amino--7-(4·Ga-2-isoindolin-4-yl- Phenyl)-4-methyl-7,8-dichloro- 611-° ratio of [4,3-<1]^1 dimethyl ketone, 144363.doc -11 · 201032806 2- Amino-7-(5,bis-biphenyl-2-yl)-4-mercapto-7,8-di-rho-6H-0 ratio bite [4,3-d]°^ °-5 -ketone, 2-amino-7-[2-(4-chloro-pyridin-3-yl)-4-fluoro-phenyl]-4-indolyl-7,8-dihydro-6H-pyridinium[ 4,3-d]pyrimidin-5-one, 2-amino- 7-(5,2'-di-n-31-decyloxy-biphenyl-2-yl)-4-methyl-7,8 -dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-(5,4'-di- gas-21-methyl-biphenyl-2-yl)- 4-methyl-7,8-dihydro-6Η-πϋ and [4,3-d]n-densidine-5-one, 2-amino-7-(5-fluoro-2'-methoxy -biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino--7- (4-gas -2 -°密17定-5-yl-phenyl)-4-A -7,8--SL ~ 6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-[4-fluoro-2-(2-methoxypyridin-3- -Phenyl]-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino--7-(5-gas-3^ Methyl-biphenyl-2-yl)-4-methyl-7,8-monomethyl-6H-pyrido[4,3-d]pyrimidin-5-one, (R)-2-amino- 6-(3-Amino-propyl)-7-[4-gas-2-(6-fluorenyl-D-pyridin-2-yl)-phenyl]-4-methyl-7,8- Dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-(4-aza-2-ntt* octa-3-yl-phenyl)-4-indenyl -7,8- —wind-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-(5,2'-difluoro-4'-indenyl-biphenyl- 2-yl)-4-mercapto-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-[4-fluoro-2-(1) -mercapto-lH-η-pyrazol-4-yl)-phenyl]-4-oxime 144363.doc -12- 201032806 -7,8-dihydro-6H-n ratio bite [4,3-d ]〇f ς2-Amino-7-[4-Ga-2-(1 Η-β than sal-4-odor, + soil)~ Benyl]-4-Methyl-7,8-dihydrogen -6Η-° ratio bite [4,3-d] bite-5-_, 2, amine _4-mercapto-7-(5,2',3'-trifluoro-brand Let-2-yl)-7,8-dihydro-6Η-α ratio. And [4,3-d] mouth. _5_ketone, 2-amino-7-(2-bromo-4-fluoro-phenyl)methyl-6-(2-indolyl-2-morphin-4-yl-propyl)- 7,8-Dihydro·6Η-° ratio bite and 丨L,3~d]pyrimidine_5_ ketone, 2-amino-7-(3'-didecylamino group_5_气牌# 3 fluoro-linked stupid _2_yl)_4_ fluorenyl-7,8-dihydro-6Η-11 than bite [4,3-d] squirting 5-keto, 2-amino-7-[2 -(2,4-dimethoxy)-glycol-phenyl]-4_methyl-7,8-dioxin-6H-pyrido[4,3-d]pyrimidin-one, 2-amino-7- [4-Fluoro-2-(5-methoxybihabine's pyridine-3-yl)-phenyl]_4_methyl-7,8-dihydro-6H-pyrido[4,3d] Pyrimidine _5__, 2-amino-7-(4-fluoro-2-pyrimidin-5-yl-stupyl)-4-mercapto-6-(2-mercapto-2-m-lin-4- Base-propyl)-78- - M , , 虱_6H1 bite and [4,3-d] bleed _5· ketone, 2-amino-7-[4-fluoro-2·(2·methoxy Base_spiro-3-ylphenyl η 6-(2-methyl-2-morpholin-4-yl-propyl)·78-dihydrooropyrimidine-5-one, 2-amino-7-(5 3._methoxy-biphenyl-based)_4•mercapto-2-morphin-4-yl-propyl)_78__舒^ 曱嗣, , 8-m-dec, 3,^ (R )_2_Amino_7_[4·Fluoro-2_(4)methoxymethyl-methyl ketone]_4_methyl_7,8·2 Hydrogen scar (4),) - stupid 144363.doc .13- 201032806 2 -Amino-7-(4- gas-2-butan-3-yl-phenyl)-4-methyl-7,8-di Wind-6Η-°Λ° and [4,3-d]e bite-5-ketone, 5 - ( 2,4 -2 blankety-5-isopropyl-phenyl)-4-(4 - Or a pharmaceutically acceptable salt or prodrug thereof; and (b) an mTOR inhibitor, which is a veolimus , rapamycin, ascomycin, CCI-779, ABT578, SAR543, AP23573, AP23841, AZD08055 or OSI027. 8. Use of a combination of a first pharmaceutical component and a second pharmaceutical component for the manufacture of a medicament for the treatment of a proliferative disorder, wherein the first pharmaceutical component is an Hsp90 inhibitor, which is of formula (III) Compound Ra Ο (III) or a pharmaceutically acceptable salt or prodrug thereof, wherein the Ra is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) CVC6 alkoxy, 144363.doc -14- 201032806 (5) Mercaptan, (6) C1 - C 6姨*-based mercaptan, (7) Substituted or unsubstituted Cl_c6 fluorenyl, (8) Amine or substituted amine group, (9) a substituted or unsubstituted aryl group, (10) a substituted or unsubstituted heteroaryl group, and (11) a substituted or unsubstituted heterocyclic group; R 4 being hydrogen or a substituted or unsubstituted crC 6 alkyl group; R5 is hydrogen, alkyl, alkoxy, or halo; R6, R7, R8, and R9 are each independently selected from hydrogen, alkyl, alkoxy, self-substituted, substituted or unsubstituted aryl And a group consisting of a substituted or unsubstituted heteroaryl group; the limitation is that if the Ra is an amine group and R6, R7, R8 and R9 are all hydrogen, then R5 is not hydrogen, alkyl, alkoxy or halogen a base, or a compound of formula (E): (E) wherein R3 is selected from the group consisting of methylaminocarbonylCH3CH2NHC(=0)-, ethylaminocarbonylCH3CH2NHC(=0)-, propylaminocarbonylCH3CH2CH2NH2NHC(=〇)-, or isopropylamino Carbonyl (ch3) 2chnhc(=o)-), 144363.doc 201032806 R8 is selected from thiol, ethyl, isopropyl, bromo or chloro; and -R9 is CHzNRWR11 or -NR^R11, wherein substituted amine --nrMr1 1 is morpholinyl, hexahydropyridyl, piperazinyl, pyrrolidinyl, ethylamino, isopropylamino, diethylamino, cyclohexylamino, cyclopentylamino, Methoxyethylamino, hexahydropyridin-4-yl, N-ethinyl piperazinyl, N-mercaptopiperazinyl, decylsulfonylamino, thiomorpholinyl, thiopental a dioxide, 4-transethylethylhexahydro-β-indenyl or 4-pyridylhexahydropyridinyl, or a pharmaceutically acceptable salt or prodrug thereof, and wherein the second pharmaceutical component Is an mTOR inhibitor. 9. 10. The use of claim 8 wherein the mT〇R inhibitor is everolimus, rapamycin, ascomycin, CCI_779, ABT578, SAR543, AP23573, AP23841, AZD08055 or OSI027. The use of claim 9, wherein the compound of formula (m) of the drug is (R)-2-amino-7-[2-(2-fluoro-acridin-3-yl)-phenyl]_4_A Base _7,8_ dihydro-6 Η-. Bis-[4,3-d]pyrimidin-5-one, (S)-2-Amino-64-yl-7-[4-fluoro-2-(2-fluoro]- _3_yl)-phenyl 4-methyl-7,8-dihydro-6H_acridine And [4,3_d] 啶 巧 ketone, W-2-amino-7-[4-fluoro_2_(2_fluoro_pyridine_3_yl)-stupyl] oxime methyl 7.8-dihydro- 6H-pyrido[4,3_d]pyrimidin-5one, soil _7,8-monooxo-pyridyl[4,3_d]pyridinium i, (8) rhyme·7_[peak methoxy m group) _基基] ice methyl 7.8- 虱-6Η_pyrido[4,3_d]pyrimidine _5-one, 144363.doc * 16 - 201032806 (R)-2-amino-7-[4-fluoro- 2-(6-methoxypyridin-2-yl)-phenyl]-4-mercapto-7,8-dihydro-6H-D ratio bite [4,3-d]w close bite-5 - Stuffed 1, 2-Amino-7-[4-lac-2-(6-methoxy-0-But-2-yl)-phenyl]-4,6-dimercapto-7,8- Dihydro-6Η-ΠΛ bite and [4,3-d] mouth bite 5-ketone, 2-amino-7-[4-gas-2-(2-gas-0 ratio bit-3-yl)- Phenyl]-4,6-dimercapto-, 7,8-dihydro-6H-. ratio. And [4,3-d] shouted to bite 5-keto, 2-amino-7-[4-disorganized-2-(6-methyllacyl. than tert-2-yl)phenyl]-4- Methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one, 2-amino-7-[2-(6-decyloxy-0 ratio °-2 -yl)-phenyl]-4-mercapto-7,8-dihydro-611-.比定[4,3-d]°_n定-5-ketone, (R)-2-amino-7-[4-fluoro-2-(6-methoxypyrazin-2-yl) -phenyl]-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-[4- gas-2-(6 -曱oxy-π ratio ° Qin-2-yl)-phenyl]-4,6-dimercapto-7,8-dihydro-6Η-pyrido[4,3-d]pyrimidin-5-one , 2-amino-7-[2-(2-decyloxy-Dtb σ-3-yl)-phenyl]-4-indolyl-7,8-dihydro-6Η-° ratio bite [4 , 3-d] ° dense. Ding-5-keto, ® 2-amino-7-(5,2'-difluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H- ° ratio [4,3-(1]. Mi 17--5-one, 2-amino- 7-(5-aero-2·-di-rhodooxybiphenyl-2-yl)-4-methyl -7,8-dihydro-6 Η-σ is more than 唆[4,3-d] yupt-5-_, 2_amino- 7- [2-(2 - gas-0 ratio ° -3- 4-)-phenyl-phenyl]-4-mercapto-7,8-dihydro-6Η-ΠΛ-[4,3-(1], yt-5-one, 2-amino- 7-[ 4-Gas-2-(6-murine-π-predative-3-yl)phenyl]-4methyl-7,8-dihydro-6Η-σ is more than [4,3-d]°. -5-ketone, 144363.doc -17- 201032806 2 -amino- 7-(4-disorgano-2-isosalin-4-yl-phenyl)-4-indolyl-7,8-di-mouse- 6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-(5,3'-difluoro-biphenyl-2-yl)-4-mercapto-7,8- Dihydro-6H-0 is more than a bite [4,3-d] ° 唆-5-one, 2-amino- 7- [2-(4- gas--0 σ--3-yl-phenyl ]-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino--7-(5,2^di- 3 -methoxy) -biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-(5,4'- Difluoro-2'-mercapto-biphenyl-2-yl)-4-methyl- 7,8-Dihydro-61"1-° ratio °[4,3-(1] mouth bite-5-ketone, 2-amino group-7- (5-gas-21-曱乳-linked Benzene-2-yl)-4-methyl-7,8-diaza-6Η-Π is more than bite [4,3-(1]° 密-5-ketone, 2-amino-7-(4 -Gas-2-°3⁄4 σ定-5-yl-phenyl)-4-methyl-7,8-diqi_611-11 than bite [4,3-(1]°密唆-5- Ketone, 2-amino-7-[4- gas-2-(2-methyllacyl-pypto-3-yl)-phenyl]-4-mercapto-7,8-dihydro-611- More than bite [4,3-(1]° sessile 5-ketone, 2-amino-7-(5-fluoro-3'-decyloxy-biphenyl-2-yl)-4-methyl Base-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, (R)-2-amino-6-(3-amino-propyl)-7-[ 4-gas-2-(6-decyloxy-.pyridin-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidine -5-keto; 2-amino- 7-(4-gas-2-0-butoxy-3-phenyl-phenyl)-4-mercapto-7,8-di-rho-6-p-beta ratio [4,3-(1]° 密定-5-ketone, 2-amino- 7-(5,2'-di------methyl-biphenyl-2-yl)-4-fluorenyl -7,8-two 144363.doc -18- 201032806 Nitrogen-6H-° ratio bite [4,3-d]°^bit-5-嗣' 2-amino-7-[4-fluoro-2- (1-methyl-1H-pyrazolyl)phenyl]_4indolyl-7,8-dihydro-6H- Pyrido[4,3-d]pyrimidine-5-3⁄4,2-amino-7-[4-fluoro-2-(1Η-0-pyrazol-4-yl)phenylidene-4-methyl-7 8-hydrogen -6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-4-methyl-7-(5,2',3'-trifluoro-biphenyl-2-yl)78 _Red 6H-pyrido[4,3-d]pyrimidin-5-one, .u methyl_2_morpholine·4-yl-propyl)-7,8-dihydro-6H-pyrido[4,3-d]pyrimidine 5 -2-amino-7-(3 dimethyl Aminoamino-5-fluoro-bi-quinone-2-yl)-4-mercapto-7,8·dihydro-6Η-° ratio bite [4,3-d]° dense β--5-_ , 2-amino-7-[2-(2,4-dimethoxyoxy-propenyl-5-yl)-4-fluoro-phenylmethyl-7,8-dihydro-6Η-. Bis-pyrene[4,3-d] 嚷 2_Amino-7 fluoro-o-methoxy ' 7,8-dihydro-6H-pyrido[4,3-d]pyrimidine bauxite-4 -methyl-2-amino-7-(4-fluoro-2-pyrimidin-5-yl-cage)-4-methyl-6-(2.methyl-2-morpholin-4-yl-propyl )-7,8-di AVT ketone, 11 6Η1 bite and [4,3 bite ·5_oxy-° ratio bite base, 8-di-3-yl)-phenyl]_4_methyl gas-6H- Pyrido[4,3·^ 2-amino-7-[4-fluoro-2-(2-methyl-6-(2-methyl-2-morphin-4-yl-propylpyrimidin-5-one, ~2-yl)-4-methyl_6 (2A-° ratio bite [4,34] pyrimidine, 5 2-amino-7-(5-gas-3'-methoxy-biphenyl Benzyl-2-morphin-4-yl-propyl)-7,8-dihydrone, 144363.doc 19. 201032806 (R)-2-Amino-H4 prepared 2_(4)methoxymethyl_2n-yl] -4·Methyl-7,8-dihydro·6Η_Π ratio bite [43_d] mouth bite _5_ketone, 2_amino-7*fluoro-2-furan-3-yl-phenyl)-4_ Indole _7,8 dihydro -6 Η-α ratio bite [4,3-d] bleed _5-ketone, 5-(2,4-dihydroxy-5-isopropyl-phenyl) ice ( 4- morpholine 4-methylphenyl)-isoxazole-3-carboxylic acid acetaminophen, or a pharmaceutically acceptable salt or prodrug thereof. 11. The use of claim 8, wherein the 111 cesium Ruler inhibitor Is the use of everolimus. 12. The use of claim 10 in combination with the rapamycin derivative of formula j• Ri system ch3 or c3.6 alkynyl group, X system = 0, (H, H) or (Η, ΟΗ), R2 system Η or -CH2-CH2-OH, 3-hydroxy-2·(hydroxy fluorenyl)_2 _ 曱 丙 丙 或 四 四 四 四 四 四 四 四 四 , , , , , , , , , , , , , , X X X X X X 144 144 144 144 144 144 144 144 144 144 144 144 144 144 144 144 144 144 144 144 (: 113. 13 The use of claim 8, wherein treating the proliferative disorder is treating tumor, osteoarthritis, leukemia, angiogenesis, dryness, restenosis, scleroderma or fibrosis. Use of the medicament comprising the compound of formula (ΙΠ) as the first pharmaceutical component and the medicament is administered together with the mTOR inhibitor as a mono-pharmaceutical composition. 15. The use of claim 8, wherein the medicament A compound of the formula (ιπ) is included as the first pharmaceutical component and the drug is administered as a separate composition with the singapore 11 inhibitor. 16. The use of the formula 8 wherein the drug comprises the formula (1) The compound of the compound is used as the "Hai-Pharma" component and the drug is administered sequentially with the mT〇R inhibitor. The combination of the p9〇 inhibitor and the mT〇R inhibitor Use for the manufacture of a medicament for the treatment of a proliferative disease. The sputum group comprises: (a) a first pharmaceutical composition comprising an HsP90 inhibitor of the compound of the formula (1), Ra η 18. A kit of parts selected from the group consisting of (I) pharmaceutically acceptable salts or prodrugs selected from the group consisting of: 144363.doc -21. 201032806 (1) hydrogen, (2) halogen, (3) meridine, (4) (^-(:6 alkoxy, (5) mercaptan, (6) mercapto mercaptan, ( 7) substituted or unsubstituted alkyl, (8) amino or substituted amine, (9) substituted or unsubstituted aryl, oxime (10) substituted or unsubstituted heteroaryl, and 11) a substituted or unsubstituted heterocyclic group; R is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted C1-C6 alkyl, (3) substituted or unsubstituted c2_C6 alkenyl, (4) Substituted or unsubstituted C2-C6 alkynyl, (5) Substituted or unsubstituted C3-C7 cycloalkyl, hydrazone (6) substituted or unsubstituted (^-cycloalkenyl, ( 7) a substituted or unsubstituted aryl group, (8) a substituted or unsubstituted heteroaryl group, and (9) a substituted or unsubstituted heterocyclic group; 1^ is selected from the group consisting of: 1) Substituted or unsubstituted C3_C7 naphthenes (2) Substituted or unsubstituted 6-(:7-cycloalkenyl, 144363.doc •22· 201032806 (3) substituted or unsubstituted aryl, (4) substituted or unsubstituted heteroaryl And (5) a substituted or unsubstituted heterocyclic group; and the limitation is that if the Ra is an amine group, Rb is not a phenyl group, a 4-alkyl-phenyl group, a 4-oxooxy-phenyl group, Or a 4-halo-phenyl* or a compound of formula (E): R3 is selected from the group consisting of decylaminocarbonyl ch3ch2nhc(=o)-, ethylaminocarbonylch3ch2nhc(=o)-, propylaminocarbonylch3ch2ch2nhc(=〇)-, or isopropylaminocarbonyl (ch3) 2chnhc(=o)-), R8 is selected from methyl, ethyl, isopropyl, bromo or chloro; and R9 is -CH2NR1GR" or -NR1GRn, wherein substituted amino-NRWr1 1 is morpholinyl, hexahydropyridyl, piperazinyl , pyrrolidinyl, ethylamino, isopropylamino, diethylamino, cyclohexylamino, cyclopentylamino, methoxyethylamino, hexahydropyridin-4-yl, N - ethyl piperazinyl, N-mercaptopiperazinyl, methylsulfonylamino, thiomorpholinyl, thiomorphyl-dioxide, 4-aminoethylhexahydrocarbyl Or 4-transbasic hexahydrogen. A pyridyl group, or a pharmaceutically acceptable salt or prodrug thereof, 144363.doc -23- 201032806 which is present in a second pharmaceutically acceptable carrier and (b) a mT〇R inhibitor. 19. The kit of claim 18, wherein the Hsp90 inhibitor is (R)-2-amino-7-[2-(2-fluoro-Bist _3_yl)-phenyl]_4•methyl _ 7 8 Hydrogen-6Η-^Π定[4,3-d] shouting _5-ketone, (S)-2-amino-6-f-yl-7·[4-fluoro-2_(2·fluoro "Bit _3_yl" _phenyl]_ 4-methyl-7,8-dihydro-6Η-pyrido[4,3_d]pyrimidin-5-one, (R)-2-amino-7 -[4-Fluoro.2-(2-Fluorine-Bit_3_yl)-phenyl]_4methyl-7,8-dihydro-611-» than bite [4,3-(1] mouth _5_ketone, (R)-2-amino-7-(2-di-4-oxo-phenyl) winter [(8) small (4-methoxyphenyl)-ethyl]-4-A Benzyl-7,8-dihydrotaphthylpyridinium[4,3_d]pyridin-5-one, (R)-2-amino-7-[2-(6-methoxy-D-pyridine) 2_基)_笨基]_4methyl_ 7.8-dihydro-6H-"bipyridyl[4,3-d]pyrimidin-5-one, (R)4-amino-7-[4- Fluorine 2_(6-methoxy-α-pyridinyl-2-phenylphenyl-4-methyl-7,8-dihydro-6Η-pyrido[4,3-d]pyrimidinone, 2-amino-7- [4-Fluoro-2-(6-methoxybendazim-2-yl)-pupidyl 4 6-dimethyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidinone, 2- Amino-7-[4-fluoro-2-(2-fluoro"(Bityl)-phenyl]_4,6-didecyl- 7.8-dihydro-6H-pyrido[4,3-d Pyrimidine 5-ketone, 2-amino-7-[4-fluoro-2-(6-methoxyacridinyl I)phenyl]methylene methyl 7.8-dihydropyrido[4,3-(1] Pyrimidine _5(611)-ketone, 2-amino-7-[2,(6-methoxy-decyl-2-yl)-phenyl]_4.methyl_78_dihydro-6H-pyrido[4 ,3-d]pyrimidine _5 ketone, (R)-2-amino-M4•fluoro~2 methoxy-terminal 2-yl)-phenyl]_4_ 144363.doc -24· 201032806 methyl-7 ,8-Dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-Amino-7-[4-Ga-2-(6-曱乳--0 唤-2- Base)-phenyl]-4,6-dimethyl-7,8-dihydro-6Η-σ ratio bite [4,3-d] shout-5-one, 2-amino group-7. 2_(2_曱oxy-σ-precipitate-3-yl)-phenyl]·4-methyl-7,8-dihydro-6Η-° ratio of [4,3-d] pyridin-5- Ketone, 2-amino-7-(5,21-dim-diphenyl-2-yl)-4-methyl-7,8-dichloro-6H·° than 唆[4,3-d] pain Indole-5-one, 2-amino- 7-(5-rat-2'·disorder methoxy-biphenyl-2-yl)-4-methyl-7,8·~ dihydro-6Η- Pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-[2-(2-milo-pyramid-3-yl)-4-a-phenyl]-4-indenyl · 7,8, dinitro-611-吼-deposited [4,3-<1] mouth-dip-5-嗣, 2-amino--7- [4- disorder-2-(6-milk-ϋ 〇定·3-yl)-phenyl]-4-mercapto-7,8-dihydro-6Η-σ& sigma-[4,3-d] yodo-5-one, 2-amino--7 - (4-murine-2-isoindolin-4-yl-phenyl)-4-methyl-7,8-dichloro-6 Η·σ ratio and [4,3-d] mouth-dip-5 -ketone, 2-amino-7-(5,3'-di-biphenyl-2-yl)-4-methyl-7,8-diaza-6 Η-port ratio [定[4, 3-(1]° 密σ定-5-_, 2·amino group - 7·[2·(4 - milk-. Benzene-3-yl)-4-a-phenyl]-4-methyl-7,8-dihydro-6Η-σΛ σ定和[4,3-(!]嘴.定-5-ketone, 2-Amino-7-(5,2f-disorder-3'-methoxy-biphenyl-2-yl)-4-mercapto-7,8-dihydro-6Η-σΛ bite [4, 3-d]^^-5·ketone, 2-amino-7-(5,41-disorgano-2 '-methylbiphenyl-2 ·yl)-4 -fluorenyl 7,8-dihydro- 6Η-σΛσ定[4,3-(1] continued °-5-keto, 2-amino- 7-(5-aero-2'-decyloxy-biphenyl-2-yl)-4 Mercapto-7,8-dichloro- 144363.doc •25· 201032806 6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-(4-gas-2 - mouth bite -5-yl-phenyl)-4-methyl-7,8-dipho-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-[4- gas- 2-(2-oxo-° ratio bit-3-yl)-phenyl]-4-mercapto-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one , 2 -Amino-7-(5-Gas- 3'-methoxy-biphenyl-2-yl)-4-methyl-7,8-dichloro-6H-pyrido[4,3-d Pyrimidine-5-one, (R)-2-amino-6-(3-amino-propyl)·7-[4-gas-2-(6-decyloxy-0-pyridin-2- -Phenyl]-4-methyl-7,8-dihydro-6H-acridino[4,3-d]pyrimidin-5-one, 2-amino-7-(4- gas-2 - ° than bite-3-base - Phenyl)-4-mercapto-7,8-di-mouse-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-(5,2'-difluoro-4 '-Methyl-biphenyl-2-yl)-4-mercapto-7,8-dihydro-6Η-αϋ°[4,3-d]°Bite-5-one, 2-Amino -7-[4-fluoro-2-(1-methyl-1H-.pyrazol-4-yl)-phenyl]-4-methyl-7,8-diaza-6 Η-.弁[4,3 - d ] mouth bite-5-tan' 2-amino-7-[4-rat-2-(111-11 than 〇-4-yl)-phenyl]-4-methyl -7,8-Dihydro-6H-° ratio bite [4,3-d]D-Bite-5-one, 2-amino-4-mercapto-7-(5,2',31-three Gas-biphenyl-2-yl)-7,8-dichloro-6Η-Π is more than bite [4,3-d]a dimethyl 5-ketone, 2-amino-7-(2-bromo- 4-fluoro-phenyl)-4-methyl-6-(2-mercapto-2-morpholin-4-yl-propyl)-7,8-di-rho--6H-. 3-d] Mouth -5 -5-阙, 2-amino- 7-(3^-dimethylamino-5-a-biphenyl-2-yl)-4-indenyl-7,8-di Hydrogen-6Η-Π is bitten and [4,3-d]°^ bites 5-ketone, 144363.doc -26- 201032806 2-Amino-7-[2-(2,4-dimethoxy-唆5-yl)-4-fluoro-phenyl]_4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino--7 - [4-gas-2-(5-methyllacyl-n ratio bite_3_yl)-phenyl ]曱基_ 7,8-Dihydro-6Η-° ratio bite [4,3-d] sputum _5-ketone, 2·amino-7-(4-fluoro-2-pyrimidin-5-yl -phenyl)_4-mercapto-6-(2-methyl-2-morphin-4-yl-propyl)-7,8-dihydro-6H-d ratio bite [4,3-d] Chito- 5-ketone, 2-amino-7-[4-fluoro-2-(2-methyllacyl-π ratio _3_yl)-phenyl]-4-mercapto-6-(2 -Methyl-2-methylindole·_4-yl-propyl)-7,8-dihydro-6H-0 ratio bite [4,3-d] mouth bite 5-keto, 2-amino-7 -(5-fluoro-3'.methoxy-biphenyl-2-yl)-4-methyl-6-(2-methyl_2· 琳琳-4·-yl-propyl)-7,8 -Dihydro-6H-° ratio bite [4,3_d] mouth bite 5--, (R)-2-amino-7-[4-fluoro-2-(4-methoxy-5-oxime -Pyrimidin-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one, 2-amino-7-( 4-fluoro-2-furan-3-ylphenyl)-4-mercapto-7,8-dihydro-6H-° ratio bite [4,3-(1] mouth bite_5_ class, 5- (2,4-dihydroxy-5-isopropyl-styl)>4(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-decanoic acid acetaminophen or its medicine An acceptable salt or prodrug; and the mTOR inhibitors are everolimus, rapamycin, ascomycin, CCI-779, ABT578, SAR543, AP23573, AP23841 AZD08055 or OSI027 〇20· a combination, which is as follows: 144363.doc • 27· 201032806 (a) an Hsp90 inhibitor compound; and W- or a plurality of pharmaceutical active i· ACE inhibitors selected from the group consisting of: ii Adenosine kinase-inhibitor; iii. adjuvant; iv. adrenal cortical antagonist; v. AKT pathway inhibitor; vi. alkylating agent; vii. angiogenesis inhibitor; viii. angiogenesis-inhibiting steroid; Anti-androgen; X. anti-estrogen; xi. anti-high blood; xii. anti-leukemia compound; xiii · antimetabolite; xiv. anti-proliferative antibody; XV. apoptosis inducer; xvi. Body antagonist; xvii·Aurora kinase inhibitor; xviii. aromatase inhibitor; xix. biological response modifier; XX. bisphosphonate; xxi. Bruton's tyrosine kinase (BTK) inhibitor; Xxii. Calcine neuron inhibitor; 144363.doc •28- 201032806 xxiii. CaM kinase II inhibitor; xxiv. CD45 cool aminase inhibitor; xxv. CDC25 nitrite inhibitor; xxvi. Agent; ^ xxvii. Dry/lower Protein or lipid kinase activity or protein or lipid. Compounds of phosphatase activity, other anti-angiogenic compounds or compounds that induce cell division processes; xxviii. Modulators for the regulation of genistein, olomoucine And/or a cool acid amide inhibitor; xxix. cyclooxygenase inhibitor; XXX. cRAF kinase inhibitor; xxxi. cyclin-dependent kinase inhibitor; xxxii. cysteine protease inhibitor; xxxiii DN entrant; xxxiv. DNA strand cleavage agent; XXXV. E3 ligase inhibitor; ❷ xxxvi. EDG binder; xxxvii. endocrine hormone; , xxxviii. Compound which is dry, reduces or inhibits epidermal growth factor family activity; Xxxix. 醯 醯-transferase inhibitor; xl. Flk-1 kinase inhibitor; xli. Compound that targets, decreases or inhibits Flt-3 activity; xlii. gonadorelin agonist; 144363.doc •29·201032806 xliii·glycogen synthase kinase-3 (GSK3) inhibitor; xliv. heparanase inhibitor; xlv. for the treatment of hematological malignancies; xlvi·histone醯-based enzyme (HDAC) inhibitor; xlvii · corticosteroid-containing implant; xlviii. Ι-κ Β-α kinase inhibitor (IKK); xlix. insulin receptor tyrosine kinase inhibitor; 1. c- JimN-terminal kinase (jNK) kinase inhibitor; li. microtubule binder; lii. mitogenic protein (MAp) kinase_inhibitor; liii. MDM2 inhibitor; liv. MEK inhibitor; Acid amine peptidase inhibitor; lvi. matrix metalloproteinase inhibitor (ΜΜρ) inhibitor; lvii. monoclonal antibody; lviii.NGFR uric acid kinase kinase; lix. p38 MAP kinase inhibitor, including SApK2/ P38 kinase inhibitor; lx. p56 tyrosine kinase inhibitor; lxi. PDGFR valine kinase inhibitor; lxii. fat-filled inositol 3-cultivator inhibitor; lxiii. luciferase inhibitor; lxiv. Dynamic therapy; lxv. initial agent; 144363.doc .30· 201032806 lxvi. Protein phosphatase inhibitors, including PP1 and PP2 inhibitors and tyrosine phosphatase inhibitors; lxvii. PKC inhibitors and PKC δ kinase inhibitors; Lxviii. polyamine synthesis inhibitor; lxix. protein body inhibitor; lxx. PTP1B inhibition Lxxi. protein cool amino acid kinase inhibitors, including SRC family glutamate kinase inhibitors; Syk tyrosine kinase inhibitors; and JAK-2 and / or JAK-3 tyrosine kinase inhibitors; lxxii. Inhibitor of Ras oncogene subtype; lxxiii. retinoid; lxxiv. ribonucleotide reductase inhibitor; lxxv. RNA polymerase II elongation inhibitor; lxxvi. S-adenosylmethionine defibrase inhibitor ; lxxvii. serine/threonine kinase inhibitor; lxxviii. somatostatin receptor antagonist; 0 lxxix. sterol biosynthesis inhibitor; lxxx. telomerase inhibitor; lxxxi. topoisomerase Inhibitor; lxxxii. Tumor cell destructive therapeutic agent; lxxxiii. VEGF or VEGFR monoclonal antibody; lxxxiv. VEGFR citrate kinase inhibitor; lxxxv. RANKL inhibitor; and mixtures thereof; Can be used simultaneously, in parallel, separately or sequentially. 144363.doc -31 -